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  • Molecular Fitness Landscapes from High-Coverage Sequence Profiling
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Celia Blanco, Evan Janzen, Abe Pressman, Ranajay Saha, Irene A. Chen

    The function of fitness (or molecular activity) in the space of all possible sequences is known as the fitness landscape. Evolution is a random walk on the fitness landscape, with a bias toward climbing hills. Mapping the topography of real fitness landscapes is fundamental to understanding evolution, but previous efforts were hampered by the difficulty of obtaining large, quantitative data sets. The accessibility of high-throughput sequencing (HTS) has transformed this study, enabling large-scale enumeration of fitness for many mutants and even complete sequence spaces in some cases. We review the progress of high-throughput studies in mapping molecular fitness landscapes, both in vitro and in vivo, as well as opportunities for future research. Such studies are rapidly growing in number. HTS is expected to have a profound effect on the understanding of real molecular fitness landscapes.

    更新日期:2019-11-18
  • Split Green Fluorescent Proteins: Scope, Limitations, and Outlook
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Matthew G. Romei, Steven G. Boxer

    Many proteins can be split into fragments that spontaneously reassemble, without covalent linkage, into a functional protein. For split green fluorescent proteins (GFPs), fragment reassembly leads to a fluorescent readout, which has been widely used to investigate protein–protein interactions. We review the scope and limitations of this approach as well as other diverse applications of split GFPs as versatile sensors, molecular glues, optogenetic tools, and platforms for photophysical studies.

    更新日期:2019-11-18
  • How Good Can Single-Particle Cryo-EM Become? What Remains Before It Approaches Its Physical Limits?
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Robert M. Glaeser

    Impressive though the achievements of single-particle cryo–electron microscopy are today, a substantial gap still remains between what is currently accomplished and what is theoretically possible. As is reviewed here, twofold or more improvements are possible as regards (a) the detective quantum efficiency of cameras at high resolution, (b) converting phase modulations to intensity modulations in the image, and (c) recovering the full amount of high-resolution signal in the presence of beam-induced motion of the specimen. In addition, potential for improvement is reviewed for other topics such as optimal choice of electron energy, use of aberration correctors, and quantum metrology. With the help of such improvements, it does not seem to be too much to imagine that determining the structural basis for every aspect of catalytic control, signaling, and regulation, in any type of cell of interest, could easily be accelerated fivefold or more.

    更新日期:2019-11-18
  • Membrane Electroporation and Electropermeabilization: Mechanisms and Models
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Tadej Kotnik, Lea Rems, Mounir Tarek, Damijan Miklavčič

    Exposure of biological cells to high-voltage, short-duration electric pulses causes a transient increase in their plasma membrane permeability, allowing transmembrane transport of otherwise impermeant molecules. In recent years, large steps were made in the understanding of underlying events. Formation of aqueous pores in the lipid bilayer is now a widely recognized mechanism, but evidence is growing that changes to individual membrane lipids and proteins also contribute, substantiating the need for terminological distinction between electroporation and electropermeabilization. We first revisit experimental evidence for electrically induced membrane permeability, its correlation with transmembrane voltage, and continuum models of electropermeabilization that disregard the molecular-level structure and events. We then present insights from molecular-level modeling, particularly atomistic simulations that enhance understanding of pore formation, and evidence of chemical modifications of membrane lipids and functional modulation of membrane proteins affecting membrane permeability. Finally, we discuss the remaining challenges to our full understanding of electroporation and electropermeabilization.

    更新日期:2019-11-18
  • Giant Vesicles and Their Use in Assays for Assessing Membrane Phase State, Curvature, Mechanics, and Electrical Properties
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Rumiana Dimova

    Giant unilamellar vesicles represent a promising and extremely useful model biomembrane system for systematic measurements of mechanical, thermodynamic, electrical, and rheological properties of lipid bilayers as a function of membrane composition, surrounding media, and temperature. The most important advantage of giant vesicles over other model membrane systems is that the membrane responses to external factors such as ions, (macro)molecules, hydrodynamic flows, or electromagnetic fields can be directly observed under the microscope. Here, we briefly review approaches for giant vesicle preparation and describe several assays used for deducing the membrane phase state and measuring a number of material properties, with further emphasis on membrane reshaping and curvature.

    更新日期:2019-11-18
  • Figure 1 Theory Meets Figure 2 Experiments in the Study of Gene Expression
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Rob Phillips, Nathan M. Belliveau, Griffin Chure, Hernan G. Garcia, Manuel Razo-Mejia, Clarissa Scholes

    It is tempting to believe that we now own the genome. The ability to read and rewrite it at will has ushered in a stunning period in the history of science. Nonetheless, there is an Achilles’ heel exposed by all of the genomic data that has accrued: We still do not know how to interpret them. Many genes are subject to sophisticated programs of transcriptional regulation, mediated by DNA sequences that harbor binding sites for transcription factors, which can up- or down-regulate gene expression depending upon environmental conditions. This gives rise to an input–output function describing how the level of expression depends upon the parameters of the regulated gene—for instance, on the number and type of binding sites in its regulatory sequence. In recent years, the ability to make precision measurements of expression, coupled with the ability to make increasingly sophisticated theoretical predictions, has enabled an explicit dialogue between theory and experiment that holds the promise of covering this genomic Achilles’ heel. The goal is to reach a predictive understanding of transcriptional regulation that makes it possible to calculate gene expression levels from DNA regulatory sequence. This review focuses on the canonical simple repression motif to ask how well the models that have been used to characterize it actually work. We consider a hierarchy of increasingly sophisticated experiments in which the minimal parameter set learned at one level is applied to make quantitative predictions at the next. We show that these careful quantitative dissections provide a template for a predictive understanding of the many more complex regulatory arrangements found across all domains of life.

    更新日期:2019-11-18
  • Mammalian Respiratory Complex I Through the Lens of Cryo-EM
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Ahmed-Noor A. Agip, James N. Blaza, Justin G. Fedor, Judy Hirst

    Single-particle electron cryomicroscopy (cryo-EM) has led to a revolution in structural work on mammalian respiratory complex I. Complex I (mitochondrial NADH:ubiquinone oxidoreductase), a membrane-bound redox-driven proton pump, is one of the largest and most complicated enzymes in the mammalian cell. Rapid progress, following the first 5-Å resolution data on bovine complex I in 2014, has led to a model for mouse complex I at 3.3-Å resolution that contains 96% of the 8,518 residues and to the identification of different particle classes, some of which are assigned to biochemically defined states. Factors that helped improve resolution, including improvements to biochemistry, cryo-EM grid preparation, data collection strategy, and image processing, are discussed. Together with recent structural data from an ancient relative, membrane-bound hydrogenase, cryo-EM on mammalian complex I has provided new insights into the proton-pumping machinery and a foundation for understanding the enzyme's catalytic mechanism.

    更新日期:2019-11-18
  • Single-Molecule Studies on the Protein Translocon
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Anne-Bart Seinen, Arnold J.M. Driessen

    Single-molecule studies provide unprecedented details about processes that are difficult to grasp by bulk biochemical assays that yield ensemble-averaged results. One of these processes is the translocation and insertion of proteins across and into the bacterial cytoplasmic membrane. This process is facilitated by the universally conserved secretion (Sec) system, a multi-subunit membrane protein complex that consists of dissociable cytoplasmic targeting components, a molecular motor, a protein-conducting membrane pore, and accessory membrane proteins. Here, we review recent insights into the mechanisms of protein translocation and membrane protein insertion from single-molecule studies.

    更新日期:2019-11-18
  • Mechanisms of Sensory Discrimination: Insights from Drosophila Olfaction
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Lukas N. Groschner, Gero Miesenböck

    All an animal can do to infer the state of its environment is to observe the sensory-evoked activity of its own neurons. These inferences about the presence, quality, or similarity of objects are probabilistic and inform behavioral decisions that are often made in close to real time. Neural systems employ several strategies to facilitate sensory discrimination: Biophysical mechanisms separate the neuronal response distributions in coding space, compress their variances, and combine information from sequential observations. We review how these strategies are implemented in the olfactory system of the fruit fly. The emerging principles of odor discrimination likely apply to other neural circuits of similar architecture.

    更新日期:2019-11-18
  • How the Genome Folds: The Biophysics of Four-Dimensional Chromatin Organization
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Jyotsana J. Parmar, Maxime Woringer, Christophe Zimmer

    The genetic information that instructs transcription and other cellular functions is carried by the chromosomes, polymers of DNA in complex with histones and other proteins. These polymers are folded inside nuclei five orders of magnitude smaller than their linear length, and many facets of this folding correlate with or are causally related to transcription and other cellular functions. Recent advances in sequencing and imaging-based techniques have enabled new views into several layers of chromatin organization. These experimental findings are accompanied by computational modeling efforts based on polymer physics that can provide mechanistic insights and quantitative predictions. Here, we review current knowledge of the main levels of chromatin organization, from the scale of nucleosomes to the entire nucleus, our current understanding of their underlying biophysical and molecular mechanisms, and some of their functional implications.

    更新日期:2019-11-18
  • Helicase Mechanisms During Homologous Recombination in Saccharomyces cerevisiae
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    J. Brooks Crickard, Eric C. Greene

    Helicases are enzymes that move, manage, and manipulate nucleic acids. They can be subdivided into six super families and are required for all aspects of nucleic acid metabolism. In general, all helicases function by converting the chemical energy stored in the bond between the gamma and beta phosphates of adenosine triphosphate into mechanical work, which results in the unidirectional movement of the helicase protein along one strand of a nucleic acid. The results of this translocation activity can range from separation of strands within duplex nucleic acids to the physical remodeling or removal of nucleoprotein complexes. In this review, we focus on describing key helicases from the model organism Saccharomyces cerevisiae that contribute to the regulation of homologous recombination, which is an essential DNA repair pathway for fixing damaged chromosomes.

    更新日期:2019-11-18
  • Generalized Born Implicit Solvent Models for Biomolecules
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Alexey V. Onufriev, David A. Case

    It would often be useful in computer simulations to use an implicit description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation and can be very efficient compared to the explicit treatment of the solvent. Here, we review a particular class of so-called fast implicit solvent models, generalized Born (GB) models, which are widely used for molecular dynamics (MD) simulations of proteins and nucleic acids. These approaches model hydration effects and provide solvent-dependent forces with efficiencies comparable to molecular-mechanics calculations on the solute alone; as such, they can be incorporated into MD or other conformational searching strategies in a straightforward manner. The foundations of the GB model are reviewed, followed by examples of newer, emerging models and examples of important applications. We discuss their strengths and weaknesses, both for fidelity to the underlying continuum model and for the ability to replace explicit consideration of solvent molecules in macromolecular simulations.

    更新日期:2019-11-18
  • An NMR View of Protein Dynamics in Health and Disease
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Ashok Sekhar, Lewis E. Kay

    Biological molecules are often highly dynamic, and this flexibility can be critical for function. The large range of sampled timescales and the fact that many of the conformers that are continually explored are only transiently formed and sparsely populated challenge current biophysical approaches. Solution nuclear magnetic resonance (NMR) spectroscopy has emerged as a powerful method for characterizing biomolecular dynamics in detail, even in cases where excursions involve short-lived states. Here, we briefly review a number of NMR experiments for studies of biomolecular dynamics on the microsecond-to-second timescale and focus on applications to protein and nucleic acid systems that clearly illustrate the functional relevance of motion in both health and disease.

    更新日期:2019-11-18
  • Biophysics of Chromatin Dynamics
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Beat Fierz, Michael G. Poirier

    Nucleosomes and chromatin control eukaryotic genome accessibility and thereby regulate DNA processes, including transcription, replication, and repair. Conformational dynamics within the nucleosome and chromatin structure play a key role in this regulatory function. Structural fluctuations continuously expose internal DNA sequences and nucleosome surfaces, thereby providing transient access for the nuclear machinery. Progress in structural studies of nucleosomes and chromatin has provided detailed insight into local chromatin organization and has set the stage for recent in-depth investigations of the structural dynamics of nucleosomes and chromatin fibers. Here, we discuss the dynamic processes observed in chromatin over different length scales and timescales and review current knowledge about the biophysics of distinct structural transitions.

    更新日期:2019-11-18
  • Raman Imaging of Small Biomolecules
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Yihui Shen, Fanghao Hu, Wei Min

    Imaging techniques greatly facilitate the comprehensive knowledge of biological systems. Although imaging methodology for biomacromolecules such as protein and nucleic acids has been long established, microscopic techniques and contrast mechanisms are relatively limited for small biomolecules, which are equally important participants in biological processes. Recent developments in Raman imaging, including both microscopy and tailored vibrational tags, have created exciting opportunities for noninvasive imaging of small biomolecules in living cells, tissues, and organisms. Here, we summarize the principle and workflow of small-biomolecule imaging by Raman microscopy. Then, we review recent efforts in imaging, for example, lipids, metabolites, and drugs. The unique advantage of Raman imaging has been manifested in a variety of applications that have provided novel biological insights.

    更新日期:2019-11-18
  • Polarizable Force Fields for Biomolecular Simulations: Recent Advances and Applications
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Zhifeng Jing, Chengwen Liu, Sara Y. Cheng, Rui Qi, Brandon D. Walker, Jean-Philip Piquemal, Pengyu Ren

    Realistic modeling of biomolecular systems requires an accurate treatment of electrostatics, including electronic polarization. Due to recent advances in physical models, simulation algorithms, and computing hardware, biomolecular simulations with advanced force fields at biologically relevant timescales are becoming increasingly promising. These advancements have not only led to new biophysical insights but also afforded opportunities to advance our understanding of fundamental intermolecular forces. This article describes the recent advances and applications, as well as future directions, of polarizable force fields in biomolecular simulations.

    更新日期:2019-11-18
  • Programming Structured DNA Assemblies to Probe Biophysical Processes
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Eike-Christian Wamhoff, James L. Banal, William P. Bricker, Tyson R. Shepherd, Molly F. Parsons, Rémi Veneziano, Matthew B. Stone, Hyungmin Jun, Xiao Wang, Mark Bathe

    Structural DNA nanotechnology is beginning to emerge as a widely accessible research tool to mechanistically study diverse biophysical processes. Enabled by scaffolded DNA origami in which a long single strand of DNA is weaved throughout an entire target nucleic acid assembly to ensure its proper folding, assemblies of nearly any geometric shape can now be programmed in a fully automatic manner to interface with biology on the 1–100-nm scale. Here, we review the major design and synthesis principles that have enabled the fabrication of a specific subclass of scaffolded DNA origami objects called wireframe assemblies. These objects offer unprecedented control over the nanoscale organization of biomolecules, including biomolecular copy numbers, presentation on convex or concave geometries, and internal versus external functionalization, in addition to stability in physiological buffer. To highlight the power and versatility of this synthetic structural biology approach to probing molecular and cellular biophysics, we feature its application to three leading areas of investigation: light harvesting and nanoscale energy transport, RNA structural biology, and immune receptor signaling, with an outlook toward unique mechanistic insight that may be gained in these areas in the coming decade.

    更新日期:2019-11-18
  • Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Moutusi Manna, Tuomo Nieminen, Ilpo Vattulainen

    Cell signaling controls essentially all cellular processes. While it is often assumed that proteins are the key architects coordinating cell signaling, recent studies have shown more and more clearly that lipids are also involved in signaling processes in a number of ways. Lipids do, for instance, act as messengers, modulate membrane receptor conformation and dynamics, and control membrane receptor partitioning. Further, through structural modifications such as oxidation, the functions of lipids as part of signaling processes can be modified. In this context, in this article we discuss the understanding recently revealed by atomistic and coarse-grained computer simulations of nanoscale processes and underlying physicochemical principles related to lipids’ functions in cellular signaling.

    更新日期:2019-11-18
  • Interrogating the Structural Dynamics and Energetics of Biomolecular Systems with Pressure Modulation
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Roland Winter

    High hydrostatic pressure affects the structure, dynamics, and stability of biomolecular systems and is a key parameter in the context of the exploration of the origin and the physical limits of life. This review lays out the conceptual framework for exploring the conformational fluctuations, dynamical properties, and activity of biomolecular systems using pressure perturbation. Complementary pressure-jump relaxation studies are useful tools to study the kinetics and mechanisms of biomolecular phase transitions and structural transformations, such as membrane fusion or protein and nucleic acid folding. Finally, the advantages of using pressure to explore biomolecular assemblies and modulate enzymatic reactions are discussed.

    更新日期:2019-11-18
  • Regulation of Transmembrane Signaling by Phase Separation
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Lindsay B. Case, Jonathon A. Ditlev, Michael K. Rosen

    Cell surface transmembrane receptors often form nanometer- to micrometer-scale clusters to initiate signal transduction in response to environmental cues. Extracellular ligand oligomerization, domain-domain interactions, and binding to multivalent proteins all contribute to cluster formation. Here we review the current understanding of mechanisms driving cluster formation in a series of representative receptor systems: glycosylated receptors, immune receptors, cell adhesion receptors, Wnt receptors, and receptor tyrosine kinases. We suggest that these clusters share properties of systems that undergo liquid–liquid phase separation and could be investigated in this light.

    更新日期:2019-11-18
  • RNA-Mediated Virus Assembly: Mechanisms and Consequences for Viral Evolution and Therapy
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Reidun Twarock, Peter G. Stockley

    Viruses, entities composed of nucleic acids, proteins, and in some cases lipids lack the ability to replicate outside their target cells. Their components self-assemble at the nanoscale with exquisite precision—a key to their biological success in infection. Recent advances in structure determination and the development of biophysical tools such as single-molecule spectroscopy and noncovalent mass spectrometry allow unprecedented access to the detailed assembly mechanisms of simple virions. Coupling these techniques with mathematical modeling and bioinformatics has uncovered a previously unsuspected role for genomic RNA in regulating formation of viral capsids, revealing multiple, dispersed RNA sequence/structure motifs [packaging signals (PSs)] that bind cognate coat proteins cooperatively. The PS ensemble controls assembly efficiency and accounts for the packaging specificity seen in vivo. The precise modes of action of the PSs vary between viral families, but this common principle applies across many viral families, including major human pathogens. These insights open up the opportunity to block or repurpose PS function in assembly for both novel antiviral therapy and gene/drug/vaccine applications.

    更新日期:2019-11-18
  • Structure and Assembly of the Nuclear Pore Complex
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Bernhard Hampoelz, Amparo Andres-Pons, Panagiotis Kastritis, Martin Beck

    Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange. They are exceptionally large protein complexes that fuse the inner and outer nuclear membranes to form channels across the nuclear envelope. About 30 different protein components, termed nucleoporins, assemble in multiple copies into an intricate cylindrical architecture. Here, we review our current knowledge of the structure of nucleoporins and how those come together in situ. We delineate architectural principles on several hierarchical organization levels, including isoforms, posttranslational modifications, nucleoporins, and higher-order oligomerization of nucleoporin subcomplexes. We discuss how cells exploit this modularity to faithfully assemble NPCs.

    更新日期:2019-11-18
  • Hybrid Live Cell–Supported Membrane Interfaces for Signaling Studies
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2019-05-14
    Kabir H. Biswas, Jay T. Groves

    A wide range of cell–microenvironmental interactions are mediated by membrane-localized receptors that bind ligands present on another cell or the extracellular matrix. This situation introduces a number of physical effects including spatial organization of receptor–ligand complexes and development of mechanical forces in cells. Unlike traditional experimental approaches, hybrid live cell–supported lipid bilayer (SLB) systems, wherein a live cell interacts with a synthetic substrate supported membrane, allow interrogation of these aspects of receptor signaling. The SLB system directly offers facile control over the identity, density, and mobility of ligands used for engaging cellular receptors. Further, application of various nano- and micropatterning techniques allows for spatial patterning of ligands. In this review, we describe the hybrid live cell–SLB system and its application in uncovering a range of spatial and mechanical aspects of receptor signaling. We highlight the T cell immunological synapse, junctions formed between EphA2- and ephrinA1-expressing cells, and adhesions formed by cadherin and integrin receptors.

    更新日期:2019-11-18
  • Transcription Dynamics in Living Cells.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2016-05-06
    Tineke L Lenstra,Joseph Rodriguez,Huimin Chen,Daniel R Larson

    The transcription cycle can be roughly divided into three stages: initiation, elongation, and termination. Understanding the molecular events that regulate all these stages requires a dynamic view of the underlying processes. The development of techniques to visualize and quantify transcription in single living cells has been essential in revealing the transcription kinetics. They have revealed that (a) transcription is heterogeneous between cells and (b) transcription can be discontinuous within a cell. In this review, we discuss the progress in our quantitative understanding of transcription dynamics in living cells, focusing on all parts of the transcription cycle. We present the techniques allowing for single-cell transcription measurements, review evidence from different organisms, and discuss how these experiments have broadened our mechanistic understanding of transcription regulation.

    更新日期:2019-11-01
  • Structural Symmetry in Membrane Proteins.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Lucy R Forrest

    Symmetry is a common feature among natural systems, including protein structures. A strong propensity toward symmetric architectures has long been recognized for water-soluble proteins, and this propensity has been rationalized from an evolutionary standpoint. Proteins residing in cellular membranes, however, have traditionally been less amenable to structural studies, and thus the prevalence and significance of symmetry in this important class of molecules is not as well understood. In the past two decades, researchers have made great strides in this area, and these advances have provided exciting insights into the range of architectures adopted by membrane proteins. These structural studies have revealed a similarly strong bias toward symmetric arrangements, which were often unexpected and which occurred despite the restrictions imposed by the membrane environment on the possible symmetry groups. Moreover, membrane proteins disproportionately contain internal structural repeats resulting from duplication and fusion of smaller segments. This article discusses the types and origins of symmetry in membrane proteins and the implications of symmetry for protein function.

    更新日期:2019-11-01
  • The Synaptic Vesicle Release Machinery.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Josep Rizo,Junjie Xu

    Extensive research has yielded crucial insights into the mechanism of neurotransmitter release, and working models for the functions of key proteins involved in release. The SNAREs Syntaxin-1, Synaptobrevin, and SNAP-25 play a central role in membrane fusion, forming SNARE complexes that bridge the vesicle and plasma membranes and that are disassembled by NSF-SNAPs. Exocytosis likely starts with Syntaxin-1 folded into a self-inhibited closed conformation that binds to Munc18-1. Munc13s open Syntaxin-1, orchestrating SNARE complex assembly in an NSF-SNAP-resistant manner together with Munc18-1. In the resulting primed state, with partially assembled SNARE complexes, fusion is inhibited by Synaptotagmin-1 and Complexins, which also perform active functions in release. Upon influx of Ca(2+), Synaptotagmin-1 activates fast release, likely by relieving the inhibition caused by Complexins and cooperating with the SNAREs in bringing the membranes together. Although alternative models exist and fundamental questions remain unanswered, a definitive description of the basic release mechanism may be available soon.

    更新日期:2019-11-01
  • Regulation of Rad6/Rad18 Activity During DNA Damage Tolerance.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Mark Hedglin,Stephen J Benkovic

    Replicative polymerases (pols) cannot accommodate damaged template bases, and these pols stall when such offenses are encountered during S phase. Rather than repairing the damaged base, replication past it may proceed via one of two DNA damage tolerance (DDT) pathways, allowing replicative DNA synthesis to resume. In translesion DNA synthesis (TLS), a specialized TLS pol is recruited to catalyze stable, yet often erroneous, nucleotide incorporation opposite damaged template bases. In template switching, the newly synthesized sister strand is used as a damage-free template to synthesize past the lesion. In eukaryotes, both pathways are regulated by the conjugation of ubiquitin to the PCNA sliding clamp by distinct E2/E3 pairs. Whereas monoubiquitination by Rad6/Rad18 mediates TLS, extension of this ubiquitin to a polyubiquitin chain by Ubc13-Mms2/Rad5 routes DDT to the template switching pathway. In this review, we focus on the monoubiquitination of PCNA by Rad6/Rad18 and summarize the current knowledge of how this process is regulated.

    更新日期:2019-11-01
  • Specification of Architecture and Function of Actin Structures by Actin Nucleation Factors.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Colleen T Skau,Clare M Waterman

    The actin cytoskeleton is essential for diverse processes in mammalian cells; these processes range from establishing cell polarity to powering cell migration to driving cytokinesis to positioning intracellular organelles. How these many functions are carried out in a spatiotemporally regulated manner in a single cytoplasm has been the subject of much study in the cytoskeleton field. Recent work has identified a host of actin nucleation factors that can build architecturally diverse actin structures. The biochemical properties of these factors, coupled with their cellular location, likely define the functional properties of actin structures. In this article, we describe how recent advances in cell biology and biochemistry have begun to elucidate the role of individual actin nucleation factors in generating distinct cellular structures. We also consider how the localization and orientation of actin nucleation factors, in addition to their kinetic properties, are critical to their ability to build a functional actin cytoskeleton.

    更新日期:2019-11-01
  • Structure Principles of CRISPR-Cas Surveillance and Effector Complexes.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-07
    Tsz Kin Martin Tsui,Hong Li

    The pathway of CRISPR-Cas immunity redefines the roles of RNA in the flow of genetic information and ignites excitement for next-generation gene therapy tools. CRISPR-Cas machineries offer a fascinating set of new enzyme assemblies from which one can learn principles of molecular interactions and chemical activities. The interference step of the CRISPR-Cas immunity pathway congregates proteins, RNA, and DNA into a single molecular entity that selectively destroys invading nucleic acids. Although much remains to be discovered, a picture of how the interference process takes place is emerging. This review focuses on the current structural data for the three known types of RNA-guided nucleic acid interference mechanisms. In it, we describe key features of individual complexes and we emphasize comparisons across types and along functional stages. We aim to provide readers with a set of core principles learned from the three types of interference complexes and a deep appreciation of the diversity among them.

    更新日期:2019-11-01
  • Single-Cell Physiology.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-03-10
    Sattar Taheri-Araghi,Steven D Brown,John T Sauls,Dustin B McIntosh,Suckjoon Jun

    Single-cell techniques have a long history of unveiling fundamental paradigms in biology. Recent improvements in the throughput, resolution, and availability of microfluidics, computational power, and genetically encoded fluorescence have led to a modern renaissance in microbial physiology. This resurgence in research activity has offered new perspectives on physiological processes such as growth, cell cycle, and cell size of model organisms such as Escherichia coli. We expect these single-cell techniques, coupled with the molecular revolution of biology's recent half-century, to continue illuminating unforeseen processes and patterns in microorganisms, the bedrock of biological science. In this article we review major open questions in single-cell physiology, provide a brief introduction to the techniques for scientists of diverse backgrounds, and highlight some pervasive issues and their solutions.

    更新日期:2019-11-01
  • Photocontrollable fluorescent proteins for superresolution imaging.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2014-06-05
    Daria M Shcherbakova,Prabuddha Sengupta,Jennifer Lippincott-Schwartz,Vladislav V Verkhusha

    Superresolution fluorescence microscopy permits the study of biological processes at scales small enough to visualize fine subcellular structures that are unresolvable by traditional diffraction-limited light microscopy. Many superresolution techniques, including those applicable to live cell imaging, utilize genetically encoded photocontrollable fluorescent proteins. The fluorescence of these proteins can be controlled by light of specific wavelengths. In this review, we discuss the biochemical and photophysical properties of photocontrollable fluorescent proteins that are relevant to their use in superresolution microscopy. We then describe the recently developed photoactivatable, photoswitchable, and reversibly photoswitchable fluorescent proteins, and we detail their particular usefulness in single-molecule localization-based and nonlinear ensemble-based superresolution techniques. Finally, we discuss recent applications of photocontrollable proteins in superresolution imaging, as well as how these applications help to clarify properties of intracellular structures and processes that are relevant to cell and developmental biology, neuroscience, cancer biology and biomedicine.

    更新日期:2019-11-01
  • Molecular mechanisms of ubiquitin-dependent membrane traffic.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-02-22
    James H Hurley,Harald Stenmark

    Over the past 14 years, ubiquitination has emerged as a centrally important mechanism governing the subcellular trafficking of proteins. Ubiquitination, interaction with sorting factors that contain ubiquitin-binding domains, and deubiquitination govern the itineraries of cargo proteins that include yeast carboxypeptidase S, the epithelial sodium channel ENaC, and epidermal growth factor receptor. The molecular structures and mechanisms of the paradigmatic HECT and RING domain ubiquitin ligases, of JAMM- and USP-domain-deubiquitinating enzymes, and of numerous ubiquitin-binding domains involved in these pathways have been worked out in recent years and are described.

    更新日期:2019-11-01
  • Lipids and cholesterol as regulators of traffic in the endomembrane system.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2010-03-03
    Jennifer Lippincott-Schwartz,Robert D Phair

    The endomembrane system of eukaryotic cells uses membrane-enclosed carriers to move diverse macromolecules among different membrane-bound compartments, a requirement for cells to secrete and take up molecules from their environment. Two recycling pathways-biosynthetic and endocytic, each with specific lipid components-make up this system, with the Golgi apparatus mediating transport between the two. Here, we integrate lipid-based mechanisms into the description of this system. A partitioning model of the Golgi apparatus is discussed as a working hypothesis to explain how membrane lipids and proteins that are segregated based on lateral lipid partitioning support the unique composition of the biosynthetic and endocytic recycling pathways in the face of constant trafficking of molecular constituents. We further discuss how computational modeling can allow for interpretation of experimental findings and provide mechanistic insight into these important cellular pathways.

    更新日期:2019-11-01
  • Lessons learned from UvrD helicase: mechanism for directional movement.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2010-03-03
    Wei Yang

    How do molecular motors convert chemical energy to mechanical work? Helicases and nucleic acids offer simple motor systems for extensive biochemical and biophysical analyses. Atomic resolution structures of UvrD-like helicases complexed with DNA in the presence of AMPPNP, ADP.Pi, and Pi reveal several salient points that aid our understanding of mechanochemical coupling. Each ATPase cycle causes two motor domains to rotationally close and open. At a minimum, two motor-track contact points of alternating tight and loose attachment convert domain rotations to unidirectional movement. A motor is poised for action only when fully in contact with its track and, if applicable, working against a load. The orientation of domain rotation relative to the track determines whether the movement is linear, spiral, or circular. Motors powered by ATPases likely deliver each power stroke in two parts, before and after ATP hydrolysis. Implications of these findings for analyzing hexameric helicase, F(1)F(0) ATPase, and kinesin are discussed.

    更新日期:2019-11-01
  • Macromolecular crowding and confinement: biochemical, biophysical, and potential physiological consequences.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2008-06-25
    Huan-Xiang Zhou,Germán Rivas,Allen P Minton

    Expected and observed effects of volume exclusion on the free energy of rigid and flexible macromolecules in crowded and confined systems, and consequent effects of crowding and confinement on macromolecular reaction rates and equilibria are summarized. Findings from relevant theoretical/simulation and experimental literature published from 2004 onward are reviewed. Additional complexity arising from the heterogeneity of local environments in biological media, and the presence of nonspecific interactions between macromolecules over and above steric repulsion, are discussed. Theoretical and experimental approaches to the characterization of crowding- and confinement-induced effects in systems approaching the complexity of living organisms are suggested.

    更新日期:2019-11-01
  • Doing molecular biophysics: finding, naming, and picturing signal within complexity.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2013-03-05
    Jane S Richardson,David C Richardson

    A macromolecular structure, as measured data or as a list of coordinates or even on-screen as a full atomic model, is an extremely complex and confusing object. The underlying rules of how it folds, moves, and interacts as a biological entity are even less evident or intuitive to the human mind. To do science on such molecules, or to relate them usefully to higher levels of biology, we need to start with a natural history that names their features in meaningful ways and with multiple representations (visual or algebraic) that show some aspect of their organizing principles. The two of us have jointly enjoyed a highly varied and engrossing career in biophysical research over nearly 50 years. Our frequent changes of emphasis are tied together by two threads: first, by finding the right names, visualizations, and methods to help both ourselves and others to better understand the 3D structures of protein and RNA molecules, and second, by redefining the boundary between signal and noise for complex data, in both directions-sometimes identifying and promoting real signal up out of what seemed just noise, and sometimes demoting apparent signal into noise or systematic error. Here we relate parts of our scientific and personal lives, including ups and downs, influences, anecdotes, and guiding principles such as the title theme.

    更新日期:2019-11-01
  • Structural Biology of the Major Facilitator Superfamily Transporters.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Nieng Yan

    The ancient and ubiquitous major facilitator superfamily (MFS) represents the largest secondary transporter family and plays a crucial role in a multitude of physiological processes. MFS proteins transport a broad spectrum of ions and solutes across membranes via facilitated diffusion, symport, or antiport. In recent years, remarkable advances in understanding the structural biology of the MFS transporters have been made. This article reviews the history, classification, and general features of the MFS proteins; summarizes recent structural progress with a focus on the sugar porter family transporters exemplified by GLUT1; and discusses the molecular mechanisms of substrate binding, alternating access, and cotransport coupling.

    更新日期:2019-11-01
  • Structure and Mechanism of RNA Mimics of Green Fluorescent Protein.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Mingxu You,Samie R Jaffrey

    RNAs have highly complex and dynamic cellular localization patterns. Technologies for imaging RNA in living cells are important for uncovering their function and regulatory pathways. One approach for imaging RNA involves genetically encoding fluorescent RNAs using RNA mimics of green fluorescent protein (GFP). These mimics are RNA aptamers that bind fluorophores resembling those naturally found in GFP and activate their fluorescence. These RNA-fluorophore complexes, including Spinach, Spinach2, and Broccoli, can be used to tag RNAs and to image their localization in living cells. In this article, we describe the generation and optimization of these aptamers, along with strategies for expanding the spectral properties of their associated RNA-fluorophore complexes. We also discuss the structural basis for the fluorescence and photophysical properties of Spinach, and we describe future prospects for designing enhanced RNA-fluorophore complexes with enhanced photostability and increased sensitivity.

    更新日期:2019-11-01
  • Biophysics of Channelrhodopsin.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Franziska Schneider,Christiane Grimm,Peter Hegemann

    Channelrhodopsins (ChRs) are directly light-gated ion channels that function as sensory photoreceptors in flagellated green algae, allowing these algae to identify optimal light conditions for growth. In neuroscience, ChRs constitute the most versatile tools for the light-induced activation of selected cells or cell types with unprecedented precision in time and space. In recent years, many ChR variants have been discovered or engineered, and countless electrical and spectroscopic studies of these ChRs have been carried out, both in host cells and on purified recombinant proteins. With significant support from a high-resolution 3D structure and from molecular dynamics calculations, scientists are now able to develop models that conclusively explain ChR activation and ion conductance on the basis of chromophore isomerization, structural changes, proton transfer reactions, and water rearrangement on timescales ranging from femtoseconds to minutes.

    更新日期:2019-11-01
  • Anatomy of Nanoscale Propulsion.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Vinita Yadav,Wentao Duan,Peter J Butler,Ayusman Sen

    Nature supports multifaceted forms of life. Despite the variety and complexity of these forms, motility remains the epicenter of life. The applicable laws of physics change upon going from macroscales to microscales and nanoscales, which are characterized by low Reynolds number (Re). We discuss motion at low Re in natural and synthetic systems, along with various propulsion mechanisms, including electrophoresis, electrolyte diffusiophoresis, and nonelectrolyte diffusiophoresis. We also describe the newly uncovered phenomena of motility in non-ATP-driven self-powered enzymes and the directional movement of these enzymes in response to substrate gradients. These enzymes can also be immobilized to function as fluid pumps in response to the presence of their substrates. Finally, we review emergent collective behavior arising from interacting motile species, and we discuss the possible biomedical applications of the synthetic nanobots and microbots.

    更新日期:2019-11-01
  • Modeling Active Mechanosensing in Cell-Matrix Interactions.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-06-23
    Bin Chen,Baohua Ji,Huajian Gao

    Cells actively sense the mechanical properties of the extracellular matrix, such as its rigidity, morphology, and deformation. The cell-matrix interaction influences a range of cellular processes, including cell adhesion, migration, and differentiation, among others. This article aims to review some of the recent progress that has been made in modeling mechanosensing in cell-matrix interactions at different length scales. The issues discussed include specific interactions between proteins, the structure and mechanosensitivity of focal adhesions, the cluster effects of the specific binding, the structure and behavior of stress fibers, cells' sensing of substrate stiffness, and cell reorientation on cyclically stretched substrates. The review concludes by looking toward future opportunities in the field and at the challenges to understanding active cell-matrix interactions.

    更新日期:2019-11-01
  • Roles for Synonymous Codon Usage in Protein Biogenesis.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-03-10
    Julie L Chaney,Patricia L Clark

    Owing to the degeneracy of the genetic code, a protein sequence can be encoded by many different synonymous mRNA coding sequences. Synonymous codon usage was once thought to be functionally neutral, but evidence now indicates it is shaped by evolutionary selection and affects other aspects of protein biogenesis beyond specifying the amino acid sequence of the protein. Synonymous rare codons, once thought to have only negative impacts on the speed and accuracy of translation, are now known to play an important role in diverse functions, including regulation of cotranslational folding, covalent modifications, secretion, and expression level. Mutations altering synonymous codon usage are linked to human diseases. However, much remains unknown about the molecular mechanisms connecting synonymous codon usage to efficient protein biogenesis and proper cell physiology. Here we review recent literature on the functional effects of codon usage, including bioinformatics approaches aimed at identifying general roles for synonymous codon usage.

    更新日期:2019-11-01
  • Mechanisms of Autophagy.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-03-10
    Nobuo N Noda,Fuyuhiko Inagaki

    The formation of the autophagosome, a landmark event in autophagy, is accomplished by the concerted actions of Atg proteins. The initial step of starvation-induced autophagy in yeast is the assembly of the Atg1 complex, which, with the help of other Atg groups, recruits Atg conjugation systems and initiates the formation of the autophagosome. In this review, we describe from a structural-biological point of view the structure, interaction, and molecular roles of Atg proteins, especially those in the Atg1 complex and in the Atg conjugation systems.

    更新日期:2019-11-01
  • Contemporary NMR Studies of Protein Electrostatics.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-03-10
    Mathias A S Hass,Frans A A Mulder

    Electrostatics play an important role in many aspects of protein chemistry. However, the accurate determination of side chain proton affinity in proteins by experiment and theory remains challenging. In recent years the field of nuclear magnetic resonance spectroscopy has advanced the way that protonation states are measured, allowing researchers to examine electrostatic interactions at an unprecedented level of detail and accuracy. Experiments are now in place that follow pH-dependent (13)C and (15)N chemical shifts as spatially close as possible to the sites of protonation, allowing all titratable amino acid side chains to be probed sequence specifically. The strong and telling response of carefully selected reporter nuclei allows individual titration events to be monitored. At the same time, improved frameworks allow researchers to model multiple coupled protonation equilibria and to identify the underlying pH-dependent contributions to the chemical shifts.

    更新日期:2019-11-01
  • Biostructural Science Inspired by Next-Generation X-Ray Sources.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2015-03-10
    Sol M Gruner,Eaton E Lattman

    Next-generation synchrotron radiation sources, such as X-ray free-electron lasers, energy recovery linacs, and ultra-low-emittance storage rings, are catalyzing novel methods of biomolecular microcrystallography and solution scattering. These methods are described and future trends are predicted. Importantly, there is a growing realization that serial microcrystallography and certain cutting-edge solution scattering experiments can be performed at existing storage ring sources by utilizing new technology. In this sense, next-generation sources are serving two distinct functions, namely, provision of new capabilities that require the newer sources and inspiration of new methods that can be performed at existing sources.

    更新日期:2019-11-01
  • Biophysics. Introduction.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2013-06-27
    Ken A Dill

    更新日期:2019-11-01
  • The underappreciated role of allostery in the cellular network.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2013-03-05
    Ruth Nussinov,Chung-Jung Tsai,Buyong Ma

    Allosteric propagation results in communication between distinct sites in the protein structure; it also encodes specific effects on cellular pathways, and in this way it shapes cellular response. One example of long-range effects is binding of morphogens to cell surface receptors, which initiates a cascade of protein interactions that leads to genome activation and specific cellular action. Allosteric propagation results from combinations of multiple factors, takes place through dynamic shifts of conformational ensembles, and affects the equilibria of macromolecular interactions. Here, we (a) emphasize the well-known yet still underappreciated role of allostery in conveying explicit signals across large multimolecular assemblies and distances to specify cellular action; (b) stress the need for quantitation of the allosteric effects; and finally, (c) propose that each specific combination of allosteric effectors along the pathway spells a distinct function. The challenges are colossal; the inspiring reward will be predicting function, misfunction, and outcomes of drug regimes.

    更新日期:2019-11-01
  • Compact intermediates in RNA folding.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2010-03-03
    Sarah A Woodson

    Large noncoding RNAs fold into their biologically functional structures via compact yet disordered intermediates, which couple the stable secondary structure of the RNA with the emerging tertiary fold. The specificity of the collapse transition, which coincides with the assembly of helical domains, depends on RNA sequence and counterions. It determines the specificity of the folding pathways and the magnitude of the free energy barriers to the ensuing search for the native conformation. By coupling helix assembly with nascent tertiary interactions, compact folding intermediates in RNA also play a crucial role in ligand binding and RNA-protein recognition.

    更新日期:2019-11-01
  • Structural bioinformatics of the interactome.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2014-06-05
    Donald Petrey,Barry Honig

    The past decade has seen a dramatic expansion in the number and range of techniques available to obtain genome-wide information and to analyze this information so as to infer both the functions of individual molecules and how they interact to modulate the behavior of biological systems. Here, we review these techniques, focusing on the construction of physical protein-protein interaction networks, and highlighting approaches that incorporate protein structure, which is becoming an increasingly important component of systems-level computational techniques. We also discuss how network analyses are being applied to enhance our basic understanding of biological systems and their disregulation, as well as how these networks are being used in drug development.

    更新日期:2019-11-01
  • Equilibrium sampling in biomolecular simulations.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-03-05
    Daniel M Zuckerman

    Equilibrium sampling of biomolecules remains an unmet challenge after more than 30 years of atomistic simulation. Efforts to enhance sampling capability, which are reviewed here, range from the development of new algorithms to parallelization to novel uses of hardware. Special focus is placed on classifying algorithms--most of which are underpinned by a few key ideas--in order to understand their fundamental strengths and limitations. Although algorithms have proliferated, progress resulting from novel hardware use appears to be more clear-cut than from algorithms alone, due partly to the lack of widely used sampling measures.

    更新日期:2019-11-01
  • RNA folding: conformational statistics, folding kinetics, and ion electrostatics.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2008-06-25
    Shi-Jie Chen

    RNA folding is a remarkably complex problem that involves ion-mediated electrostatic interaction, conformational entropy, base pairing and stacking, and noncanonical interactions. During the past decade, results from a variety of experimental and theoretical studies pointed to (a) the potential ion correlation effect in Mg2+-RNA interactions, (b) the rugged energy landscapes and multistate RNA folding kinetics even for small RNA systems such as hairpins and pseudoknots, (c) the intraloop interactions and sequence-dependent loop free energy, and (d) the strong nonadditivity of chain entropy in RNA pseudoknot and other tertiary folds. Several related issues, which have not been thoroughly resolved, require combined approaches with thermodynamic and kinetic experiments, statistical mechanical modeling, and all-atom computer simulations.

    更新日期:2019-11-01
  • Amphipols from A to Z.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-05-07
    J-L Popot,T Althoff,D Bagnard,J-L Banères,P Bazzacco,E Billon-Denis,L J Catoire,P Champeil,D Charvolin,M J Cocco,G Crémel,T Dahmane,L M de la Maza,C Ebel,F Gabel,F Giusti,Y Gohon,E Goormaghtigh,E Guittet,J H Kleinschmidt,W Kühlbrandt,C Le Bon,K L Martinez,M Picard,B Pucci,J N Sachs,C Tribet,C van Heijenoort,F Wien,F Zito,M Zoonens

    Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep integral membrane proteins (MPs) water soluble. In this review, we discuss their structure and solution behavior; the way they associate with MPs; and the structure, dynamics, and solution properties of the resulting complexes. All MPs tested to date form water-soluble complexes with APols, and their biochemical stability is in general greatly improved compared with MPs in detergent solutions. The functionality and ligand-binding properties of APol-trapped MPs are reviewed, and the mechanisms by which APols stabilize MPs are discussed. Applications of APols include MP folding and cell-free synthesis, structural studies by NMR, electron microscopy and X-ray diffraction, APol-mediated immobilization of MPs onto solid supports, proteomics, delivery of MPs to preexisting membranes, and vaccine formulation.

    更新日期:2019-11-01
  • Protein self-organization: lessons from the min system.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-05-07
    Martin Loose,Karsten Kruse,Petra Schwille

    One of the most fundamental features of biological systems is probably their ability to self-organize in space and time on different scales. Despite many elaborate theoretical models of how molecular self-organization can come about, only a few experimental systems of biological origin have so far been rigorously described, due mostly to their inherent complexity. The most promising strategy of modern biophysics is thus to identify minimal biological systems showing self-organized emergent behavior. One of the best-understood examples of protein self-organization, which has recently been successfully reconstituted in vitro, is represented by the oscillations of the Min proteins in Escherichia coli. In this review, we summarize the current understanding of the mechanism of Min protein self-organization in vivo and in vitro. We discuss the potential of the Min oscillations to sense the geometry of the cell and suggest that spontaneous protein waves could be a general means of intracellular organization. We hypothesize that cooperative membrane binding and unbinding, e.g., as an energy-dependent switch, may act as an important regulatory mechanism for protein oscillations and pattern formation in the cell.

    更新日期:2019-11-01
  • Decision making in living cells: lessons from a simple system.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-05-07
    Ido Golding

    The life cycle of bacteriophage lambda serves as a simplified paradigm for cell-fate decisions. The ongoing quantitative, high-resolution experimental investigation of this life cycle has produced some important insights in recent years. These insights have to do with the way cells choose among alternative fates, how they maintain long-term memory of their gene-expression state, and how they switch from one stable state to another. The recent studies have highlighted the role of spatiotemporal effects in cellular processes and the importance of distinguishing chemical stochasticity from possible hidden variables in cellular decision making.

    更新日期:2019-11-01
  • Proton-pumping mechanism of cytochrome C oxidase.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-05-07
    Shinya Yoshikawa,Kazumasa Muramoto,Kyoko Shinzawa-Itoh

    Cytochrome c oxidase (CcO), as the terminal oxidase of cellular respiration, coupled with a proton-pumping process, reduces molecular oxygen (O(2)) to water. This intriguing and highly organized chemical process represents one of the most critical aspects of cellular respiration. It employs transition metals (Fe and Cu) at the O(2) reduction site and has been considered one of the most challenging research subjects in life science. Extensive X-ray structural and mutational analyses have provided two different proposals with regard to the mechanism of proton pumping. One mechanism is based on bovine CcO and includes an independent pathway for the pumped protons. The second mechanistic proposal includes a common pathway for the pumped and chemical protons and is based upon bacterial CcO. Here, recent progress in experimental evaluations of these proposals is reviewed and strategies for improving our understanding of the mechanism of this physiologically important process are discussed.

    更新日期:2019-11-01
  • Respice, adspice, and prospice.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-05-07
    Harold A Scheraga

    The title, "Look to the past, Look to the present, and Look to the future," the motto of City College of New York, expresses how my family life and education led me to an academic career in physical chemistry and ultimately to a study of proteins. The economic depression of the 1930s left a lasting impression on my outlook and career aspirations. With fortunate experiences at several stages in my life, I was able to participate in the great adventure of the last half of the twentieth century: the revolution in biology that advanced the field of protein chemistry to so great an extent. The future is bright and limitless, with greater understanding of biology yet to come.

    更新日期:2019-11-01
  • Mechanosignaling to the cell nucleus and gene regulation.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-03-12
    G V Shivashankar

    Cells integrate physicochemical signals on the nanoscale from the local microenvironment, resulting in altered functional nuclear landscape and gene expression. These alterations regulate diverse biological processes including stem cell differentiation, establishing robust developmental genetic programs and cellular homeostatic control systems. The mechanisms by which these signals are integrated into the 3D spatiotemporal organization of the cell nucleus to elicit differential gene expression programs are poorly understood. In this review I analyze our current understanding of mechanosignal transduction mechanisms to the cell nucleus to induce differential gene regulation. A description of both physical and chemical coupling, resulting in a prestressed nuclear organization, is emphasized. I also highlight the importance of spatial dimension in chromosome assembly, as well as the temporal filtering and stochastic processes at gene promoters that may be important in understanding the biophysical design principles underlying mechanoregulation of gene transcription.

    更新日期:2019-11-01
  • Protein folding at the exit tunnel.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-03-05
    Daria V Fedyukina,Silvia Cavagnero

    Over five decades of research have yielded a large body of information on how purified proteins attain their native state when refolded in the test tube, starting from a chemically or thermally denatured state. Nevertheless, we still know little about how proteins fold and unfold in their natural biological habitat: the living cell. Indeed, a variety of cellular components, including molecular chaperones, the ribosome, and crowding of the intracellular medium, modulate folding mechanisms in physiologically relevant environments. This review focuses on the current state of knowledge in protein folding in the cell with emphasis on the early stage of a protein's life, as the nascent polypeptide traverses and emerges from the ribosomal tunnel. Given the vectorial nature of ribosome-assisted translation, the transient degree of chain elongation becomes a relevant variable expected to affect nascent protein foldability, aggregation propensity and extent of interaction with chaperones and the ribosome.

    更新日期:2019-11-01
  • Stochastic conformational pumping: a mechanism for free-energy transduction by molecules.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-03-01
    R Dean Astumian

    Proteins and other macromolecules can act as molecular machines that convert energy from one form to another through cycles of conformational transitions. In a macroscopically fluctuating environment or at the single-molecule level, the probability for a molecule to be in any state j fluctuates, and the probability current from any other state i to state j is given as the sum of a steady-state current and a pumped current, I(ij)=I(ss)(ij)+F(ij)dP(j)/dt, where F(ij) is the fraction of the fluctuating current into and out of state j coming directly from state i, and dP(j)/dt is the rate of change of the probability for the molecule to be in state j. If the fluctuations arise from an equilibrium source, microscopic reversibility guarantees that the time average of the pumped current is zero. If, however, the fluctuations arise due to the action of a nonequilibrium source, the time average of the pumped current is not in general zero and can be opposite in sign to the steady-state current. The pumped current provides a mechanism by which fluctuations, whether generated externally or arising from an internal nonequilibrium chemical reaction, can do electrical, mechanical, or chemical work on a system by coupling into the equilibrium conformational transitions of a protein. In this review I examine work elaborating the mechanism of stochastic pumping and also discuss a thermodynamically consistent approach for modeling the effects of dynamic disorder on enzymes and other proteins.

    更新日期:2019-11-01
  • P-type ATPases.
    Annu. Rev. Biophys. (IF 12.175) Pub Date : 2011-03-01
    Michael G Palmgren,Poul Nissen

    P-type ATPases form a large superfamily of cation and lipid pumps. They are remarkably simple with only a single catalytic subunit and carry out large domain motions during transport. The atomic structure of P-type ATPases in different conformations, together with ample mutagenesis evidence, has provided detailed insights into the pumping mechanism by these biological nanomachines. Phylogenetically, P-type ATPases are divided into five subfamilies, P1-P5. These subfamilies differ with respect to transported ligands and the way they are regulated.

    更新日期:2019-11-01
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