Is β-Catenin a Druggable Target for Cancer Therapy? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-07-02 Can Cui, Xianglian Zhou, Weidong Zhang, Yi Qu, Xisong Ke
Mutations of canonical Wnt signaling pathway genes frequently occur in cancer and lead to abnormal accumulation of the key effector β-catenin. Over the past decades, a number of Wnt inhibitors have been identified through high-throughput screenings, however, very few of them target β-catenin directly, raising questions regarding its druggability. Here, we review Wnt inhibitors with a focus on small molecules that directly bind β-catenin, discuss the druggability of β-catenin, and why it has rarely been targeted, especially in the cellular context. We also propose strategies to develop small molecule binding and depleting cellular β-catenin, which are generally applicable to other difficult-to-drug or yet-to-be-drugged targets.
From the Wave Equation to Biomolecular Structure and Dynamics Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-30 Suren A. Tatulian
The multiscale models for complex chemical systems constitute a powerful computational tool to describe biomolecular structure and dynamics, including enzymatic reactions. Here, the development of this method is presented as a miraculous chain of events, involving astoundingly lucky encounters of brilliant minds such as Planck, Schrödinger, Pauling, Karplus, Levitt, and Warshel.
Emerging Roles of Non-Coding RNA Transcription Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-28 Minna U. Kaikkonen, Karen Adelman
Metazoan genomes are broadly transcribed by RNA polymerase II (RNAPII), but surprisingly few of these RNAs encode proteins. Accordingly, there is great interest in understanding the origins and potential roles of the vast array of non-coding RNAs (ncRNAs) that are produced. We present here emerging evidence that the act of transcription and the presence of nascent RNA at a locus is often central to function, rather than specific ncRNA sequences or structures. We highlight examples wherein transcription elongation through a regulatory region modulates chromatin structure and/or transcription factor occupancy, and describe how nascent RNA contributes to the local epigenetic landscape through sequence-independent interactions with chromatin regulators. Finally, we discuss current strategies for probing the potential functions of ncRNA transcription.
Quality Control in the Endoplasmic Reticulum: Crosstalk between ERAD and UPR pathways Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-29 Jiwon Hwang, Ling Qi
Endoplasmic reticulum (ER)-associated degradation (ERAD) and the unfolded protein response (UPR) are two key quality-control machineries in the cell. ERAD is responsible for the clearance of misfolded proteins in the ER for cytosolic proteasomal degradation, while UPR is activated in response to the accumulation of misfolded proteins. It has long been thought that ERAD is an integral part of UPR because expression of many ERAD genes is controlled by UPR; however, recent studies have suggested that ERAD has a direct role in controlling the protein turnover and abundance of IRE1α, the most conserved UPR sensor. Here, we review recent advances in our understanding of IRE1α activation and propose that UPR and ERAD engage in an intimate crosstalk to define folding capacity and maintain homeostasis in the ER.
Physiological Functions of Nedd4-2: Lessons from Knockout Mouse Models Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-29 Jantina A. Manning, Sharad Kumar
Protein modification by ubiquitination plays a key evolutionarily conserved role in regulating membrane proteins. Nedd4-2, a ubiquitin ligase, targets membrane proteins such as ion channels and transporters for ubiquitination. This Nedd4-2-mediated ubiquitination provides a crucial step in controlling the membrane availability of these proteins, thus affecting their signaling and physiological outcomes. In one well-studied example, Nedd4-2 fine-tunes the physiological function of the epithelial sodium channel (ENaC), thus modulating Na+ reabsorption by epithelia to maintain whole-body Na+ homeostasis. This review summarizes the key signaling pathways regulated by Nedd4-2 and the possible implications of such regulation in various pathologies.
Gene Regulatory Network Perturbation by Genetic and Epigenetic Variation Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-22 Yongsheng Li, Daniel J. McGrail, Juan Xu, Gordon B. Mills, Nidhi Sahni, Song Yi
Gene regulatory networks underlie biological function and cellular physiology. Alternative splicing (AS) is a fundamental step in gene regulatory networks and plays a key role in development and disease. In addition to the identification of aberrant AS events, an increasing number of studies are focusing on molecular determinants of AS, including genetic and epigenetic regulators. We review here recent efforts to identify various deregulated AS events as well as their molecular determinants that alter biological functions, and discuss clinical features of AS and their druggable potential.
Reversible, Spatial and Temporal Control over Protein Activity Using Light Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-19 Mark W.H. Hoorens, Wiktor Szymanski
In biomedical sciences, the function of a protein of interest is investigated by altering its net activity and assessing the consequences for the cell or organism. To change the activity of a protein, a wide variety of chemical and genetic tools have been developed. The drawback of most of these tools is that they do not allow for reversible, spatial and temporal control. Here, we describe selected developments in photopharmacology that aim at establishing such control over protein activity through bioactive molecules with photo-controlled potency. We also discuss why such control is desired and what challenges still need to be overcome for photopharmacology to reach its maturity as a chemical biology research tool.
Epigenetic Editing: Repurposing for Rescue Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-14 Hari R. Singh
The epigenome editing framework provides an engineering approach to explore chromatin-based gene expression mechanisms. However, therapeutic utility of epigenetic editing-based systems has been lacking. A report in Cell (Liu et. al., 2018) shows that epigenetic editors can revert abnormal heterochromatin formation at the gene promoter leading to restoration of FMR1 gene expression, functionally rescuing fragile X syndrome (FXS), an otherwise unamenable genetic disorder.
Unraveling Endocrine FGF Signaling Complex to Combat Metabolic Diseases Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-06-09 Yongde Luo, Weiqin Lu, Xiaokun Li
Metabolic homeostasis is critical to cellular and organismal health. The newly revealed crystal structures of the endocrine factors FGF21 and FGF23, in association with the glycosidase coreceptor Klotho and transmembrane tyrosine kinase FGFR, set a platform for structure-based novel drug design against common metabolic disorders.
N-term 2017: Proteostasis via the N-terminus Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-09 Nico Dissmeyer, Emmanuelle Graciet, Michael J. Holdsworth, Daniel J. Gibbs
N-term 2017 was the first international meeting to bring together researchers from diverse disciplines with a shared interest in protein N-terminal modifications and the N-end rule pathway of ubiquitin-mediated proteolysis, providing a platform for interdisciplinary cross-kingdom discussions and collaborations, as well as strengthening the visibility of this growing scientific community.
The Krebs Uric Acid Cycle: A Forgotten Krebs Cycle Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-26 Jack G. Salway
Hans Kornberg wrote a paper entitled ‘Krebs and his trinity of cycles' commenting that every school biology student knows of the Krebs cycle, but few know that Krebs discovered two other cycles. These are (i) the ornithine cycle (urea cycle), (ii) the citric acid cycle (tricarboxylic acid or TCA cycle), and (iii) the glyoxylate cycle that was described by Krebs and Kornberg. Ironically, Kornberg, codiscoverer of the ‘glyoxylate cycle’, overlooked a fourth Krebs cycle – (iv) the uric acid cycle.
Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-23 Jason D. Salter, Harold C. Smith
The 11-member APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of zinc-dependent cytidine deaminases bind to RNA and single-stranded DNA (ssDNA) and, in specific contexts, modify select (deoxy)cytidines to (deoxy)uridines. In this review, we describe advances made through high-resolution co-crystal structures of APOBECs bound to mono- or oligonucleotides that reveal potential substrate-specific binding sites at the active site and non-sequence-specific nucleic acid binding sites distal to the active site. We also discuss the effect of APOBEC oligomerization on functionality. Future structural studies will need to address how ssDNA binding away from the active site may enhance catalysis and the mechanism by which RNA binding may modulate catalytic activity on ssDNA.
DNA-Based Dynamic Reaction Networks Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-21 Ting Fu, Yifan Lyu, Hui Liu, Ruizi Peng, Xiaobing Zhang, Mao Ye, Weihong Tan
Deriving from logical and mechanical interactions between DNA strands and complexes, DNA-based artificial reaction networks (RNs) are attractive for their high programmability, as well as cascading and fan-out ability, which are similar to the basic principles of electronic logic gates. Arising from the dream of creating novel computing mechanisms, researchers have placed high hopes on the development of DNA-based dynamic RNs and have strived to establish the basic theories and operative strategies of these networks. This review starts by looking back on the evolution of DNA dynamic RNs; in particular’ the most significant applications in biochemistry occurring in recent years. Finally, we discuss the perspectives of DNA dynamic RNs and give a possible direction for the development of DNA circuits.
Cap-Independent Translation: What’s in a Name? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-19 Ivan N. Shatsky, Ilya M. Terenin, Victoria V. Smirnova, Dmitri E. Andreev
Eukaryotic translation initiation relies on the m7G cap present at the 5′ end of all mRNAs. Some viral mRNAs employ alternative mechanisms of initiation based on internal ribosome entry. The ‘IRES ideology’ was adopted by researchers to explain the differential translation of cellular mRNAs when the cap recognition is suppressed. However, some cellular IRESs have already been challenged and others are awaiting their validation. As an alternative cap-independent mechanism, we propose adopting the concept of cap-independent translation enhancers (CITEs) for mammalian mRNAs. Unlike IRESs, CITEs can be located both within 5′ and 3′ UTRs and bind mRNA-recruiting translational components. The respective 5′ UTRs are then inspected by the scanning machinery essentially in the same way as under cap-dependent translation.
Does Too Much MAGIC Lead to Mitophagy? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-19 Mohamed A. Eldeeb, Richard P. Fahlman
Neurodegeneration-associated hallmarks include an abundance of protein aggregates and amelioration of mitochondrial function. Despite the knowledge of molecular counteracting mechanisms, the molecular dialogue between protein aggregate accumulation and aberrant mitochondrial import is poorly understood. Recent work unraveled a novel role for the mitochondrial import machinery in regulating cytosolic proteostasis.
KRAS Activating Signaling Triggers Arteriovenous Malformations Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-07 Feixiong Cheng, Ruth Nussinov
The underlying genetic causes and altered signaling pathways of brain arteriovenous malformations remain unknown. A study published in The New England Journal of Medicine reported that KRAS somatic mutations (p.Gly12Val/Asp) were identified in brain arteriovenous malformations of human subjects and endothelial cell-enriched cultures, which might specifically activate the MAPK (mitogen-activated protein kinase)–ERK (extracellular signal-regulated kinase) signaling pathway in brain endothelial cells.
Fatty Acid Oxidation in Cell Fate Determination Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-04 Jianhua Xiong
Mitochondrial fatty acid β-oxidation (FAO) is a major catabolic process that degrades long-chain fatty acids. Recent reports reveal a broad role for FAO in cell fate control in endothelial cells, immune cells, and cancer cells. Concurrently, unique molecular pathways influenced by FAO have been identified that alter cell fate decisions.
Concept of DNA Lesion Longevity and Chromosomal Translocations Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-04 Nicholas R. Pannunzio, Michael R. Lieber
A subset of chromosomal translocations related to B cell malignancy in human patients arises due to DNA breaks occurring within defined 20–600 base pair (bp) zones. Several factors influence the breakage rate at these sites including transcription, DNA sequence, and topological tension. These factors favor non-B DNA structures that permit formation of transient single-stranded DNA (ssDNA), making the DNA more vulnerable to agents such as the enzyme activation-induced cytidine deaminase (AID) and reactive oxygen species (ROS). Certain DNA lesions created during the ssDNA state persist after the DNA resumes its normal duplex structure. We propose that factors favoring both formation of transient ssDNA and persistent DNA lesions are key in determining the DNA breakage mechanism.
Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-04 Madhu Chaturvedi, Justin Schilling, Alexandre Beautrait, Michel Bouvier, Jeffrey L. Benovic, Arun K. Shukla
G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures. Furthermore, pepducins, aptamers, and intrabodies targeting the intracellular face of GPCRs have also been successfully utilized to modulate receptor signaling. Moreover, small molecule compounds, aptamers, and synthetic intrabodies targeting β-arrestins have also been discovered to modulate GPCR endocytosis and signaling. Here, we discuss the emerging paradigm of intracellular targeting of GPCRs, and outline the current challenges, potential opportunities, and future outlook in this particular area of GPCR biology.
Architecture of PRC2 Holo Complexes Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-03 Kendra R. Vann, Tatiana G. Kutateladze
Polycomb repressive complex 2 (PRC2) is a chief epigenetic regulator. In a new article, Chen et al. describe the crystal structure of the heterotetrameric PRC2 holo complex, which provides important mechanistic insights into the organization of its subunits and the association of PRC2 with chromatin.
Highlighting IR Spectrochemical Imaging of the Retina Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-05-02 Ebrahim Aboualizadeh, Carol J. Hirschmugl
An emerging application of mid-IR spectrochemical imaging of the retina is its utility in studying the highly localized biomolecular alterations in the chemistry of retinal cell layers associated with several pathological conditions. Spatially resolved IR images highlight simultaneous chemical composition of the entire span of the retina in a label-free manner.
Why Do Disordered and Structured Proteins Behave Differently in Phase Separation? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-30 Huan-Xiang Zhou, Valery Nguemaha, Konstantinos Mazarakos, Sanbo Qin
Intracellular membraneless organelles and their myriad cellular functions have garnered tremendous recent interest. It is becoming well accepted that they form via liquid–liquid phase separation (LLPS) of protein mixtures (often including RNA), where the organelles correspond to a protein-rich droplet phase coexisting with a protein-poor bulk phase. The major protein components contain disordered regions and often also RNA-binding domains, and the disordered fragments on their own easily undergo LLPS. By contrast, LLPS for structured proteins has been observed infrequently. The contrasting phase behaviors can be explained by modeling disordered and structured proteins, respectively, as polymers and colloids. These physical models also provide a better understanding of the regulation of droplet formation by cellular signals and its dysregulation leading to diseases.
Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-27 Caitlyn Q Herr, Robert P. Hausinger
Since their discovery in the 1960s, the family of Fe(II)/2-oxoglutarate-dependent oxygenases has undergone a tremendous expansion to include enzymes catalyzing a vast diversity of biologically important reactions. Recent examples highlight roles in controlling chromatin modification, transcription, mRNA demethylation, and mRNA splicing. Others generate modifications in tRNA, translation factors, ribosomes, and other proteins. Thus, oxygenases affect all components of molecular biology’s central dogma, in which information flows from DNA to RNA to proteins. These enzymes also function in biosynthesis and catabolism of cellular metabolites, including antibiotics and signaling molecules. Due to their critical importance, ongoing efforts have targeted family members for the development of specific therapeutics. This review provides a general overview of recently characterized oxygenase reactions and their key biological roles.
Principles of Chromosome Architecture Revealed by Hi-C Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-21 Kyle P. Eagen
Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops. Compartmentation was not dependent on CTCF or cohesin. Hi-C contact maps represent the superimposition of CTCF/cohesin-dependent and -independent folding states.
Widespread Enhancer Activity from Core Promoters Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-16 Alejandra Medina-Rivera, David Santiago-Algarra, Denis Puthier, Salvatore Spicuglia
Gene expression in higher eukaryotes is precisely regulated in time and space through the interplay between promoters and gene-distal regulatory regions, known as enhancers. The original definition of enhancers implies the ability to activate gene expression remotely, while promoters entail the capability to locally induce gene expression. Despite the conventional distinction between them, promoters and enhancers share many genomic and epigenomic features. One intriguing finding in the gene regulation field comes from the observation that many core promoter regions display enhancer activity. Recent high-throughput reporter assays along with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-related approaches have indicated that this phenomenon is common and might have a strong impact on our global understanding of genome organisation and gene expression regulation.
Suprathreshold Stochastic Resonance behind Cancer Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-14 Guillermo Rodrigo, Nigel G. Stocks
Noise in gene expression is pervasive and, in some cases, even fulfills a functional role. Cancer cell populations exploit noise to increase heterogeneity as a defense against therapies. What lies behind this picture is a phenomenon of stochastic resonance led by the collective, rather than by individual cells.
Metabolite Depletion Affects Flux Profiling of Cell Lines Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-12 A. Nilsson, J.R. Haanstra, B. Teusink, J. Nielsen
Quantifying the rate of consumption and release of metabolites (i.e., flux profiling) has become integral to the study of cancer. The fluxes as well as the growth of the cells may be affected by metabolite depletion during cultivation.
Hypothesis on the Synchronistic Evolution of Autotrophy and Heterotrophy Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-11 Kirstin Gutekunst
All life on earth requires a source of energy and organic carbon. There has been a continuous debate on whether autotrophic or heterotrophic metabolism came first. A very similar discussion exists concerning the advent of oxygenic photosynthesis and aerobic respiration. I put forward the synchronistic evolution hypothesis supposing that all metabolic processes develop in a bidirectional manner from the very first. Bidirectionality is claimed to be intrinsic to the evolution of all metabolic processes as (i) all biochemical reactions and enzymes are per se bidirectional, (ii) substrates need to be regenerated, and (iii) flux regulation requires flexibility of direction. Autotrophy and heterotrophy are thus inherent to each other. A scenario for the synchronistic development of oxygenic photosynthesis and aerobic respiration is described.
Long-Term Transcriptional Gene Silencing by RNA Viruses Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-11 Juozas Baltusnikas, Saulius Satkauskas, Kenneth Lundstrom
Long-term transcriptional gene silencing has been hampered by delivery issues. A potential solution is the application of RNA viruses that generate small RNAs without any DNA intermediate. Long-term therapy for various diseases is expected after a single administration.
Probing Ion Channel Structure and Function Using Light-Sensitive Amino Acids Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-10 Viktoria Klippenstein, Laetitia Mony, Pierre Paoletti
Approaches to remotely control and monitor ion channel operation with light are expanding rapidly in the biophysics and neuroscience fields. A recent development directly introduces light sensitivity into proteins by utilizing photosensitive unnatural amino acids (UAAs) incorporated using the genetic code expansion technique. The introduction of UAAs results in unique molecular level control and, when combined with the maximal spatiotemporal resolution and poor invasiveness of light, enables direct manipulation and interrogation of ion channel functionality. Here, we review the diverse applications of light-sensitive UAAs in two superfamilies of ion channels (voltage- and ligand-gated ion channels; VGICs and LGICs) and summarize existing UAA tools, their mode of action, potential, caveats, and technical considerations to their use in illuminating ion channel structure and function.
Conformation Polymorphism of Polyglutamine Proteins Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-07 Xinran Feng, Shouqing Luo, Boxun Lu
Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure–cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation–cytotoxicity relationship of polyQ proteins.
Structural Basis of Arrestin-Dependent Signal Transduction Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-04-07 Qiuyan Chen, Tina M. Iverson, Vsevolod V. Gurevich
Arrestins are a small family of proteins with four isoforms in humans. Remarkably, two arrestins regulate signaling from >800 G protein-coupled receptors (GPCRs) or nonreceptor activators by simultaneously binding an activator and one out of hundreds of other signaling proteins. When arrestins are bound to GPCRs or other activators, the affinity for these signaling partners changes. Thus, it is proposed that an activator alters arrestin’s ability to transduce a signal. The comparison of all available arrestin structures identifies several common conformational rearrangements associated with activation. In particular, it identifies elements that are directly involved in binding to GPCRs or other activators, elements that likely engage distinct downstream effectors, and elements that likely link the activator-binding sites with the effector-binding sites.
Unraveling the Structure and Mechanism of the MST(ery) Enzymes Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-21 Catherine L. Shelton, Audrey L. Lamb
The menaquinone, siderophore, and tryptophan (MST) enzymes transform chorismate to generate precursor molecules for the biosynthetic pathways defined in their name. Kinetic data, both steady-state and transient-state, and X-ray crystal structures indicate that these enzymes are highly conserved both in mechanism and in structure. Because these enzymes are found in pathogens but not in humans, there is considerable interest in these enzymes as drug design targets. While great progress has been made in defining enzyme structure and mechanism, inhibitor design has lagged behind. This review provides a detailed description of the evidence that begins to unravel the mystery of how the MST enzymes work, and how that information has been used in inhibitor design.
A Lethal Channel between the ATP Synthase Monomers Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-16 Salvatore Nesci
The molecular structure of the transmembrane domain of ATP synthases is responsible for the inner mitochondrial membrane bending. According to the hypothesized mechanism, ATP synthase dissociation from dimers to monomers, triggered by Ca2+ binding to F1, allows the mitochondrial permeability transition pore formation at the interface between the detached monomers.
Evolving Linear Chromosomes and Telomeres: A C-Strand-Centric View Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-14 Neal F. Lue
Recent studies have resulted in deeper understanding of a variety of telomere maintenance mechanisms as well as plausible models of telomere evolution. Often overlooked in the discussion of telomere regulation and evolution is the synthesis of the DNA strand that bears the 5′-end (i.e., the C-strand). Herein, I describe a scenario for telomere evolution that more explicitly accounts for the evolution of the C-strand synthesis machinery. In this model, CTC1-STN1-TEN1 (CST), the G-strand-binding complex that regulates primase-Pol α-mediated C-strand synthesis, emerges as a pivotal player and evolutionary link. Itself arising from RPA, CST not only coordinates telomere synthesis, but also gives rise to the POT1-TPP1 complex, which became part of shelterin and regulates telomerase in G-strand elongation.
Affimer Proteins: Theranostics of the Future? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-14 Stuart Kyle
Affimer proteins can bind to a wide variety of target molecules. They can complement and represent a promising alternative to conventional antibodies as they can target molecules with high affinity, specificity, and stability. In addition, they can be selected and expressed in bacterial and mammalian systems. Affimer protein technology shows promise as a tool in the biologist’s arsenal of the future in imaging, diagnostic, and therapeutic applications.
Homing in: Mechanisms of Substrate Targeting by Protein Kinases Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-12 Chad J. Miller, Benjamin E. Turk
Protein phosphorylation is the most common reversible post-translational modification in eukaryotes. Humans have over 500 protein kinases, of which more than a dozen are established targets for anticancer drugs. All kinases share a structurally similar catalytic domain, yet each one is uniquely positioned within signaling networks controlling essentially all aspects of cell behavior. Kinases are distinguished from one another based on their modes of regulation and their substrate repertoires. Coupling specific inputs to the proper signaling outputs requires that kinases phosphorylate a limited number of sites to the exclusion of hundreds of thousands of off-target phosphorylation sites. Here, we review recent progress in understanding mechanisms of kinase substrate specificity and how they function to shape cellular signaling networks.
The Cytokinin-Activating LOG-Family Proteins Are Not Lysine Decarboxylases Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-07 Muhammad Naseem, Elena Bencurova, Thomas Dandekar
A conserved PGGxGTxxE motif misleads the cytokinin (CK) converting LONELY GUY enzymes to be wrongly annotated as lysine decarboxylases (LDCs). However, so far PGGxGTxxE motif-containing LDCs do not show any LDC activity. Instead, they show phosphoribohydrolase activity by converting inactive CK nucleotides into active free-base forms to invoke CK responses.
Fine-Tuning Limited Proteolysis: A Major Role for Regulated Site-Specific O-Glycosylation Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-02 Christoffer K. Goth, Sergey Y. Vakhrushev, Hiren J. Joshi, Henrik Clausen, Katrine T. Schjoldager
Limited proteolytic processing is an essential and ubiquitous post-translational modification (PTM) affecting secreted proteins; failure to regulate the process is often associated with disease. Glycosylation is also a ubiquitous protein PTM and site-specific O-glycosylation in close proximity to sites of proteolysis can regulate and direct the activity of proprotein convertases, a disintegrin and metalloproteinases (ADAMs), and metalloproteinases affecting the activation or inactivation of many classes of proteins, including G-protein-coupled receptors (GPCRs). Here, we summarize the emerging data that suggest O-glycosylation to be a key regulator of limited proteolysis, and highlight the potential for crosstalk between multiple PTMs.
Native RNA-Sequencing Throws its Hat into the Transcriptomics Ring Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-03-01 Shobbir Hussain
De novo sequence-level surveys of transcriptomes have previously relied on sequencing via a DNA intermediate. While such methods can yield massive data sets, various problems mean that these do not always accurately reflect the true innate composition of transcriptomes. Enter Garalde et al., who present for the first time highly parallel native RNA-Sequencing (RNA-seq), with potentially disruptive future-implications for the transcriptomics field.
Protein Disaggregation in Multicellular Organisms Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-28 Nadinath B. Nillegoda, Anne S. Wentink, Bernd Bukau
Protein aggregates are formed in cells with profoundly perturbed proteostasis, where the generation of misfolded proteins exceeds the cellular refolding and degradative capacity. They are a hallmark of protein conformational disorders and aged and/or environmentally stressed cells. Protein aggregation is a reversible process in vivo, which counteracts proteotoxicities derived from aggregate persistence, but the chaperone machineries involved in protein disaggregation in Metazoa were uncovered only recently. Here we highlight recent advances in the mechanistic understanding of the major protein disaggregation machinery mediated by the Hsp70 chaperone system and discuss emerging alternative disaggregation activities in multicellular organisms.
SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-27 Russell A. DeBose-Boyd, Jin Ye
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.
Unravelling the Mechanisms of RNA Helicase Regulation Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-24 Katherine E. Sloan, Markus T. Bohnsack
RNA helicases are critical regulators at the nexus of multiple pathways of RNA metabolism, and in the complex cellular environment, tight spatial and temporal regulation of their activity is essential. Dedicated protein cofactors play key roles in recruiting helicases to specific substrates and modulating their catalytic activity. Alongside individual RNA helicase cofactors, networks of cofactors containing evolutionarily conserved domains such as the G-patch and MIF4G domains highlight the potential for cross-regulation of different aspects of gene expression. Structural analyses of RNA helicase–cofactor complexes now provide insight into the diverse mechanisms by which cofactors can elicit specific and coordinated regulation of RNA helicase action. Furthermore, post-translational modifications (PTMs) and long non-coding RNA (lncRNA) regulators have recently emerged as novel modes of RNA helicase regulation.
Guiding Mitotic Progression by Crosstalk between Post-translational Modifications Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-24 Sabine A.G. Cuijpers, Alfred C.O. Vertegaal
Cell division is tightly regulated to disentangle copied chromosomes in an orderly manner and prevent loss of genome integrity. During mitosis, transcriptional activity is limited and post-translational modifications (PTMs) are responsible for functional protein regulation. Essential mitotic regulators, including polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDK), as well as the anaphase-promoting complex/cyclosome (APC/C), are members of the enzymatic machinery responsible for protein modification. Interestingly, communication between PTMs ensures the essential tight and timely control during all consecutive phases of mitosis. Here, we present an overview of current concepts and understanding of crosstalk between PTMs regulating mitotic progression.
Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-22 Alec G. Trub, Matthew D. Hirschey
In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of ‘carbon stress’, similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis.
Metabolic Kinases Moonlighting as Protein Kinases Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-17 Zhimin Lu, Tony Hunter
Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes. Emerging evidence demonstrates that some metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase (KHK) isoform A (KHK-A), hexokinase (HK), and nucleoside diphosphate kinase 1 and 2 (NME1/2), that phosphorylate soluble metabolites can also function as protein kinases and phosphorylate a variety of protein substrates to regulate the Warburg effect, gene expression, cell cycle progression and proliferation, apoptosis, autophagy, exosome secretion, T cell activation, iron transport, ion channel opening, and many other fundamental cellular functions. The elevated protein kinase functions of these moonlighting metabolic enzymes in tumor development make them promising therapeutic targets for cancer.
Getting Momentum: From Biocatalysis to Advanced Synthetic Biology Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-06 Christoffel P.S. Badenhorst, Uwe T. Bornscheuer
Applied biocatalysis is driven by environmental and economic incentives for using enzymes in the synthesis of various pharmaceutical and industrially important chemicals. Protein engineering is used to tailor the properties of enzymes to catalyze desired chemical transformations, and some engineered enzymes now outperform the best chemocatalytic alternatives by orders of magnitude. Unfortunately, custom engineering of a robust biocatalyst is still a time-consuming process, but an understanding of how enzyme function depends on amino acid sequence will speed up the process. This review demonstrates how recent advances in ultrahigh-throughput screening, mutational scanning, DNA synthesis, metagenomics, and machine learning will soon make it possible to model, predict, and manipulate the relationship between protein sequence and function, accelerating the tailor design of novel biocatalysts.
Clustering of Rac1: Selective Lipid Sorting Drives Signaling Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-11-30 Kelsey N. Maxwell, Yong Zhou, John F. Hancock
The ability of lipid-anchored small GTPases to form nanometer-scale lipid domains on the cell plasma membrane (PM) is precipitating exciting new insights into membrane-anchored protein regulation. A recent article by Remorino et al. demonstrates that Rac1, similar to Ras, forms nanoclusters on the PM. The implications of these findings are discussed herein.
Methylation of Elongation Factor 1A: Where, Who, and Why? Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-02-01 Joshua J. Hamey, Marc R. Wilkins
Eukaryotic elongation factor 1A (eEF1A) is an essential and highly conserved protein involved in diverse cellular processes, including translation, cytoskeleton organisation, nuclear export, and proteasomal degradation. Recently, nine novel and site-specific methyltransferases were discovered that target eEF1A, five in yeast and four in human, making it the eukaryotic protein with the highest number of independent methyltransferases. Some of these methyltransferases show striking evolutionary conservation. Yet, they come from diverse methyltransferase families, indicating they confer competitive advantage through independent origins. As might be expected, the first functional studies of specific methylation sites found them to have distinct effects, notably on eEF1A-related processes of translation and tRNA aminoacylation. Further functional studies of sites will likely reveal other unique roles for this interesting modification.
Protein Tertiary Structure by Crosslinking/Mass Spectrometry Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-01-31 Michael Schneider, Adam Belsom, Juri Rappsilber
Observing the structures of proteins within the cell and tracking structural changes under different cellular conditions are the ultimate challenges for structural biology. This, however, requires an experimental technique that can generate sufficient data for structure determination and is applicable in the native environment of proteins. Crosslinking/mass spectrometry (CLMS) and protein structure determination have recently advanced to meet these requirements and crosslinking-driven de novo structure determination in native environments is now possible. In this opinion article, we highlight recent successes in the field of CLMS with protein structure modeling and challenges it still holds.
Mind the Organelle Gap – Peroxisome Contact Sites in Disease Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-01-31 Inês Gomes Castro, Maya Schuldiner, Einat Zalckvar
The eukaryotic cell is organized as a complex grid system where membrane-bound cellular compartments, organelles, must be localized to the right place at the right time. One way to facilitate correct organelle localization and organelle cooperation is through membrane contact sites, areas of close proximity between two organelles that are bridged by protein/lipid complexes. It is now clear that all organelles physically contact each other. The main focus of this review is contact sites of peroxisomes, central metabolic hubs whose defects lead to a variety of diseases. New peroxisome contacts, their tethering complexes and functions have been recently discovered. However, if and how peroxisome contacts contribute to the development of peroxisome-related diseases is still a mystery.
RNA Selection by PIWI Proteins Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-01-24 Alexey L. Arkov
Gene regulation by PIWI–piRNA complexes is determined by the selection of cognate target RNAs by PIWI–piRNA. What are the mechanisms for this selection? There is a rigorous multistep control in identifying target RNAs by PIWI–piRNA structures, and RNA helicases play a potentially crucial role in this process.
Oxa1 Superfamily: New Members Found in the ER Trends Biochem. Sci. (IF 15.678) Pub Date : 2018-01-12 Yuanyuan Chen, Ross E. Dalbey
Oxa1/Alb3/YidC family members promote the insertion of proteins into the mitochondrial inner membrane, the chloroplast thylakoid membrane, and the bacterial plasma membrane. Remarkably, two recent studies identify new Oxa1 homologs that reside in the endoplasmic reticulum (ER) and function in ER membrane protein biogenesis.
Replication-Coupled Nucleosome Assembly in the Passage of Epigenetic Information and Cell Identity Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-29 Albert Serra-Cardona, Zhiguo Zhang
During S phase, replicated DNA must be assembled into nucleosomes using both newly synthesized and parental histones in a process that is tightly coupled to DNA replication. This DNA replication-coupled process is regulated by multitude of histone chaperones as well as by histone-modifying enzymes. In recent years novel insights into nucleosome assembly of new H3–H4 tetramers have been gained through studies on the classical histone chaperone CAF-1 and the identification of novel factors involved in this process. Moreover, in vitro reconstitution of chromatin replication has shed light on nucleosome assembly of parental H3–H4, a process that remains elusive. Finally, recent studies have revealed that the replication-coupled nucleosome assembly is important for the determination and maintenance of cell fate in multicellular organisms.
Resolving the Gordian Knot: Srs2 Strips Intermediates Formed during Homologous Recombination Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-28 Harshad Ghodke, Jacob S. Lewis, Antoine M. van Oijen
Cells use a suite of specialized enzymes to repair chromosomal double-strand breaks (DSBs). Two recent studies describe how single-molecule fluorescence imaging techniques are used in the direct visualization of some of the key molecular steps involved. De Tullio et al. and Kaniecki et al. watch individual Srs2 helicase molecules disrupt repair intermediates formed by RPA, Rad51, and Rad52 on DNA during homologous recombination.
Paraspeckles: Where Long Noncoding RNA Meets Phase Separation Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-27 Archa H. Fox, Shinichi Nakagawa, Tetsuro Hirose, Charles S. Bond
Long noncoding RNA (lncRNA) molecules are some of the newest and least understood players in gene regulation. Hence, we need good model systems with well-defined RNA and protein components. One such system is paraspeckles – protein-rich nuclear organelles built around a specific lncRNA scaffold. New discoveries show how paraspeckles are formed through multiple RNA–protein and protein–protein interactions, some of which involve extensive polymerization, and others with multivalent interactions driving phase separation. Once formed, paraspeckles influence gene regulation through sequestration of component proteins and RNAs, with subsequent depletion in other compartments. Here we focus on the dual aspects of paraspeckle structure and function, revealing an emerging role for these dynamic bodies in a multitude of cellular settings.
MK2–TNF–Signaling Comes Full Circle Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-21 Manoj B. Menon, Matthias Gaestel
MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis – pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond.
TCR Signaling: Mechanisms of Initiation and Propagation Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-18 Adam H. Courtney, Wan-Lin Lo, Arthur Weiss
The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR.
Organization and Function of Non-dynamic Biomolecular Condensates Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-16 Jeffrey B. Woodruff, Anthony A. Hyman, Elvan Boke
Cells compartmentalize biochemical reactions using organelles. Organelles can be either membrane-bound compartments or supramolecular assemblies of protein and ribonucleic acid known as ‘biomolecular condensates’. Biomolecular condensates, such as nucleoli and germ granules, have been described as liquid like, as they have the ability to fuse, flow, and undergo fission. Recent experiments have revealed that some liquid-like condensates can mature over time to form stable gels. In other cases, biomolecular condensates solidify into amyloid-like fibers. Here we discuss the assembly, organization, and physiological roles of these more stable condensates in cells, focusing on Balbiani bodies, centrosomes, nuclear pores, and amyloid bodies. We discuss how the material properties of these condensates can be explained by the principles of liquid–liquid phase separation and maturation.
Hippo Signaling in the Immune System Trends Biochem. Sci. (IF 15.678) Pub Date : 2017-12-14 Yuchao Zhang, Haitao Zhang, Bin Zhao
Hippo signaling has a pivotal role in organ size control, tissue regeneration, and cancer. Recent studies have demonstrated critical functions of Hippo signaling in cancer immunity, innate immune responses against pathogens, and autoimmune diseases, refreshing our understanding of the implications of this pathway in the context of disease and therapy design.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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