ATP1A3 encodes the α3 isoform of Na,K-ATPase. In the brain it is expressed only in neurons. Human ATP1A3 mutations produce a wide spectrum of phenotypes, but particular syndromes are associated with unique substitutions. For arginine 756, at the junction of membrane and cytoplasmic domains, mutations produce encephalopathy during febrile infections. Here we tested the pathogenicity of p.Arg756His (R756H)

PcyA, a ferredoxin-dependent bilin pigment reductase, catalyzes the site-specific reduction of the two vinyl groups of biliverdin (BV), producing phycocyanobilin (PCB). Previous neutron crystallography detected both the neutral BV and its protonated form (BVH+) in the wild-type (WT) PcyA-BV complex, and a nearby catalytic residue Asp105 was found to have two conformations (protonated and deprotonated)

Chlamydia trachomatis (ct) is the most-reported bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Caseinolytic proteases (ClpP) from pathogenic bacteria are attractive antibiotic targets, particularly for bacterial species that form persister colonies with phenotypic resistance against common antibiotics. ClpP functions as a multi-subunit proteolytic

Transfer RNAs undergo diverse post-transcriptional modifications to regulate a myriad of cellular events including translation, stress response, and viral replication. These post-transcriptional modifications are synthesized by site-specific modification enzymes. Recent RNA sequencing techniques have revealed multiple features of tRNA such as tRNA abundance, tRNA modification, and tRNA structure. Here

Pathogenic species from the Mycobacterium genus are responsible for a number of adverse health conditions in humans and animals that threaten health security and the economy worldwide. Mycobacteria have up to five specialized secretion systems (ESX-1 to -5) that transport virulence factors across their complex cell envelope to facilitate manipulation of their environment. In pathogenic species, these

After a COVID-related hiatus, the fifth biennial symposium on Evolution and Core Processes in Gene Regulation met at the Stowers Institute in Kansas City, Missouri July 21-24, 2022. This symposium, sponsored by the American Society for Biochemistry and Molecular Biology (ASBMB), featured experts in gene regulation and evolutionary biology. Topic areas covered enhancer evolution, the cis-regulatory

Oxidation of DNA bases generates mutagenic and cytotoxic lesions that are implicated in cancer and other diseases. Oxidative base lesions, including 7,8-dihydro-8-oxoguanine (oxoG), are typically removed through base excision repair (BER). In addition, oxidized deoxynucleotides such as 8-oxo-dGTP are depleted by sanitizing enzymes to preclude DNA incorporation. While pathways that counter threats posed

Engineering new protein functionalities through the addition of non-coded amino acids is a major biotechnological endeavor that needs to overcome the natural firewalls that prevent misincorporation during natural protein synthesis. This field is in constant evolution driven by the discovery or design of new tools, many of which are based on archaeal biology. In a recent article published in JBC, one

Small Heat shock proteins (sHsps) are a family of molecular chaperones that bind non-native proteins in an ATP-independent manner. C. elegans encodes 16 different sHsps, among them Hsp17, which is evolutionarily distinct from other sHsps in the nematode. The structure and mechanism of Hsp17 and how these may differ from other sHsps remain unclear. Here, we find that Hsp17 has a distinct expression

To ensure efficient photosynthesis, chloroplast proteins need to be flexibly regulated under fluctuating light conditions. Thiol-based redox regulation plays a key role in reductively activating several chloroplast proteins in a light-dependent manner. The ferredoxin (Fd)/thioredoxin (Trx) pathway has long been recognized as the machinery that transfers reducing power generated by photosynthetic electron

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The type IIB receptor protein tyrosine phosphatases (R2B RPTPs) are cell surface transmembrane proteins that engage in cell adhesion via their extracellular domains (ECDs) and cell signaling via their cytoplasmic phosphatase domains. The ECDs of R2B RPTPs form stable, homophilic, trans interactions between adjacent cell membranes. Previous work has demonstrated how one family member, PTPRM, forms head-to-tail

S-Acylation is an essential post-translational modification, which is mediated by a family of twenty-three zDHHC enzymes in humans. Several thousand proteins are modified by S-acylation; however, we lack a detailed understanding of how enzyme-substrate recognition and specificity is achieved. Previous work showed that the ankyrin repeat domain of zDHHC17 (ANK17) recognizes a short linear motif, known

The Par complex polarizes diverse animal cells through the concerted action of multiple regulators. Binding to the multi-PDZ domain containing protein Par-3 couples the complex to cortical flows that construct the Par membrane domain. Once localized properly, the complex is thought to transition from Par-3 to the Rho GTPase Cdc42 to activate the complex. While this transition is a critical step in

The Apolipoprotein E-ε4 allele (APOE-ε4) is the strongest genetic risk factor for late onset Alzheimer disease (AD). ApoE plays a critical role in amyloid-β (Aβ) accumulation in AD, and genetic deletion of the murine ApoE gene in mouse models results in a decrease or inhibition of Aβ deposition. The association between the presence of ApoE and amyloid in amyloidoses suggests a more general role for

Crustaceans have an open vascular system in which hemocytes freely circulate in hemolymph. Hemocytes are rich in hemocyanin, a specific oxygen-transport protein in crustaceans; therefore, understanding the response of hemocytes to hypoxia is crucial. Although hemocytes take up glucose during hypoxia, the molecular mechanism of glucose uptake in crustaceans remains unclear. Herein, we identified two

Retinoid X receptors (RXR) are nuclear transcription factors that partner with other nuclear receptors to regulate numerous physiological processes. Although RXR represents a valid therapeutic target, only a few RXR-specific ligands (rexinoids) have been identified, in part due to the lack of clarity on how rexinoids selectively modulate RXR response. Previously, we showed that rexinoid UAB30 potentiates

Nudix hydrolase 7 (NUDT7) is an enzyme that hydrolyzes CoA species, is highly expressed in the liver, and resides in the peroxisomes. Peroxisomes are organelles where the preferential oxidation of dicarboxylic fatty acids occurs and where the hepatic synthesis of the primary bile acids cholic acid and chenodeoxycholic acid is completed. We previously showed that liver-specific overexpression of NUDT7

We show that T7 DNA polymerase and exonuclease domains contribute to selective error correction during DNA replication by regulating bidirectional strand transfer between the two active sites. To explore the kinetic basis for selective removal of mismatches we used a fluorescent cytosine analog (tCo) to monitor the kinetics of DNA transfer between the exonuclease and polymerase sites. We globally fit

Engineering a highly tumor microenvironment-responsive nanoplatform toward effective chemotherapy has always been a challenge in targeted cancer treatment. Metal-organic frameworks are a promising delivery system to reformulate previously approved drugs for enhanced chemotherapy, such as disulfiram (DSF). Herein, a tumor microenvironment-activated metal-organic framework-based nanoplatform DSF@MOF-199@FA

Boric acid is a vital micronutrient in animals; however, excess amounts are toxic to them. Little is known about whole-body boric acid homeostasis in animals. Seawater contains 0.4 mM boric acid, and since marine fish drink seawater, their urinary system was used here as a model of the boric acid excretion system. We determined that the bladder urine of a euryhaline pufferfish (river pufferfish, Takifugu

Interferon induced transmembrane proteins (IFITMs) are broad spectrum antiviral factors that inhibit the entry of a wide range of clinically important pathogens including influenza A virus, HIV-1 and Dengue virus. IFITMs are thought to act primarily by antagonising virus-cell membrane fusion in this regard. However, recent work on these proteins has uncovered novel post-entry viral restriction mechanisms

One of the first steps in ribosome biogenesis is transcription of the ribosomal DNA (rDNA) by RNA polymerase I (Pol I). Processing of the resultant ribosomal RNA (rRNA) begins co-transcriptionally and perturbation of Pol I transcription elongation results in defective rRNA processing. Mechanistic insight regarding the link between transcription elongation and ribosome assembly is lacking due to limited

Myxovirus resistance protein 1 (MX1) and MX2, are homologous, dynamin-like large GTPases, induced upon interferon (IFN) exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus (IAV), by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood

Recent discovery of the ribosomal protein (RP) RPL11 interacting with and inhibiting the E3 ubiquitin ligase function of MDM2 established the RP-MDM2-p53 signaling pathway, which is linked to biological events including ribosomal biogenesis, nutrient availability and metabolic homeostasis. Mutations in RPs lead to a diverse array of phenotypes known as ribosomopathies in which the role of p53 is implicated

Endometrial cancer (EC) is one of the common gynecological malignancies of which the incidence has been rising for decades. It is considered that continuously unopposed estrogen exposure is the main risk factor for EC initiation. Thus, exploring the modulation of estrogen/estrogen receptor (ERα) signaling pathway in EC would be helpful to well understand the mechanism of EC development and find the

BY-kinases constitute a family of protein tyrosine kinases that are highly conserved in the bacterial kingdom and occur most commonly as essential components of multi-component assemblies responsible for the biosynthesis, polymerization, and export of complex polysaccharides involved in biofilm or capsule formation. BY-kinase function has been attributed to a cyclic process involving formation of an

The emergence of new escape mutants of the SARS-CoV-2 virus has escalated its penetration among the human population and has reinstated its status as a global pandemic. Therefore, developing effective antiviral therapy against emerging SARS-CoV variants and other viruses in a short period of time becomes essential. Blocking SARS-CoV-2 entry into human host cells by disrupting the Spike glycoprotei

The cholesterol metabolites oxysterols play central roles in cholesterol feedback control. They modulate the activity of two master transcription factors that control cholesterol homeostatic responses, sterol regulatory element-binding protein-2 (SREBP-2) and liver X receptor (LXR). Although the role of exogenous oxysterols in regulating these transcription factors has been well established, whether

Understanding L-fucose metabolism is important because it is used as a therapy for several congenital disorders of glycosylation. Exogenous L-fucose can be activated and incorporated directly into multiple N- and O-glycans via the fucose salvage/recycling pathway. However, unlike for other monosaccharides, no mammalian L-fucose transporter has been identified. Here, we functionally screened nearly

Activation of the Wnt/β-catenin pathway regulates gene expression by promoting the formation of a β-catenin-T cell factor (TCF) complex on target enhancers. In addition to TCFs, other transcription factors interact with the Wnt/β-catenin pathway at different levels to produce tissue-specific patterns of Wnt target gene expression. The transcription factor SOX9 potently represses many Wnt target genes

Zinc fluctuations regulate key steps in late oocyte and preimplantation embryo development; however, roles for zinc in preceding stages in early ovarian follicle development, when cooperative interactions exist between the oocyte and somatic cells, are unknown. To understand the roles of zinc during early follicle development, we applied single cell X-ray fluorescence microscopy, a radioactive zinc

Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signals. We previously demonstrated that STAP-2 binds to epidermal growth factor receptor (EGFR) and facilitates its stability and activation of EGFR signaling in prostate cancer cells. Inhibition of this interaction may be a promising direction for cancer treatment. Here, we found that 2D5

Molybdenum cofactor (Moco) is a prosthetic group necessary for the activity of four unique enzymes, including the essential sulfite oxidase (SUOX-1). Moco is required for life; humans with inactivating mutations in the genes encoding Moco-biosynthetic enzymes display Moco deficiency, a rare and lethal inborn error of metabolism. Despite its importance to human health, little is known about how Moco

Eukaryotic cells harbor two DNA binding clamps, PCNA, and another clamp commonly referred to as 9-1-1 clamp. In contrast to the essential role of PCNA in DNA replication as a sliding clamp for DNA polymerase (Pol) δ, no such role in DNA synthesis has been identified for the human 9-1-1 clamp or the orthologous yeast 17-3-1 clamp. The only role identified for either the 9-1-1 or 17-3-1 clamp is in the

Efficient delivery of vitamin A to the retinal pigment epithelium is vital to the production of the light-sensitive visual chromophore 11-cis-retinal. Nevertheless, retinol binding protein 4 (RBP4) is the only known carrier of vitamin A in plasma. Here we present new findings that further characterize the visual cycle in the presence of Rbp4-deficiency. In the face of impaired delivery of retinol in

The Major Histocompatibility Complex class I (MHC-I) related protein 1 (MR1) presents small molecule metabolites, drugs, and drug-like molecules that are recognized by MR1-reactive T cells. While we have an understanding of how antigens bind to MR1 and upregulate MR1 cell surface expression, a quantitative, cell-free, assessment of MR1-ligand binding affinity was lacking. Here, we developed a fluorescence

The NLRP3 inflammasome is a critical component of innate immunity that defends the host from microbial infections. However, its aberrant activation contributes to the pathogenesis of several inflammatory diseases. Activation of the NLRP3 inflammasome induces the secretion of proinflammatory cytokines IL-1β and IL-18, and pyroptotic cell death. NLRP3 contains a leucine-rich repeat (LRR) domain at its

Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression

Site-specific recombinase Int mediates integration of the bacteriophage λ genome into the E. coli chromosome. Integration occurs once the Int tetramer, assisted by the integration host factor IHF, forms the intasome, a higher order structure, within which Int, a heterobivalent protein, interacts with two non-homologous DNA sequences: the core recombination sites and the accessory arm sites. The binding

Cancer cells, including those of prostate cancer (PCa), often hijack intrinsic cell signaling to reprogram their metabolism. Part of this reprogramming includes the activation of de novo synthesis of fatty acids that not only serve as building blocks for membrane synthesis but also as energy sources for cell proliferation. However, how de novo fatty acid synthesis contributes to PCa progression is

Hsp70s are multifunctional proteins and serve as the central hub of the protein quality control network. Hsp70s are also related to a number of diseases and have been established as drug targets. Human HspA1A (hHsp70) and HspA8 (hHsc70) are the major cytosolic Hsp70s, and they have both overlapping and distinct functions. hHsp70 contains five cysteine residues, and hHsc70 contains four cysteine residues

Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase that plays a major role in developmental processes and metabolism. The dysregulation of FGFR1 through genetic aberrations leads to skeletal and metabolic diseases as well as cancer. For this reason, FGFR1 is a promising therapeutic target, yet a very challenging one due to potential on-target toxicity. More puzzling is that both

The characterization of protein-protein interactions (PPIs) is of high value for understanding protein function. Two strategies are popular for identification of PPIs direct from the cellular environment: Affinity capture (pulldown) isolates the protein of interest with an immobilized matrix that specifically captures the target and potential partners, while in BioID genetic fusion of biotin ligase

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels whereas

Adipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes, and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the

Circulation of influenza A virus (IAV), especially within poultry and pigs, continues to threaten public health. A simple and universal detecting method is important for monitoring IAVs infection in different species. Recently, nanobodies, which show advantages of easy gene-editing and low cost of production, are a promising novel diagnostic tool for the monitoring and control of global IAVs. In the

Collagens are the most abundant proteins in the body and among the most biosynthetically complex. A molecular ensemble of over 20 endoplasmic reticulum resident proteins participates in collagen biosynthesis and contributes to heterogeneous post-translational modifications. Pathogenic variants in genes encoding collagens cause connective tissue disorders, including Osteogenesis Imperfecta, Ehlers-Danlos

The carrageenophyte red alga Chondrus crispus produces three family 16 glycoside hydrolases (CcGH16-1, -2 and -3). Phylogenetically, the red algal GH16 members are closely related to bacterial GH16 homologues from subfamilies 13 and 14, which have characterized marine bacterial β-carrageenase and β-porphyranase activities, respectively, yet the functions of these CcGH16 hydrolases have not been determined

Fasting hyperglycemia in diabetes mellitus is caused by unregulated glucagon secretion that activates gluconeogenesis (GNG) and increases the use of pyruvate, lactate, amino acids, and glycerol. Studies of GNG in hepatocytes, however, tend to test a limited number of substrates at non-physiologic concentrations. Therefore, we treated cultured primary hepatocytes with three identical substrate mixtures

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N6-methyladenosine (m6A) RNA methylation, one of the most widespread posttranscriptional modifications in eukaryotes, plays crucial roles in various developmental processes. The m6A modification process is catalyzed by a methyltransferase complex that includes Wilms tumor 1-associated protein (WTAP) as a key component. Whether the development of dental enamel is regulated by m6A RNA methylation in

The L-type Ca2+ channel CaV1.2 controls gene expression, cardiac contraction, and neuronal activity. Calmodulin (CaM) governs CaV1.2 open probability (Po) and Ca2+-dependent inactivation (CDI) but the mechanisms remain unclear. Here, we present electrophysiological data that identify a half Ca2+-saturated CaM species (Ca2/CaM) with Ca2+ bound solely at the third and fourth EF-hands (EF3 and EF4) under

The Red Blood Cell (RBC)-Omics study, part of the larger NHLBI-funded Recipient Epidemiology and Donor Evaluation Study (REDS-III), aims to understand the genetic contribution to blood donor RBC characteristics. Previous work identified donor demographic, behavioral, genetic, and metabolic underpinnings to blood donation, storage, and (to a lesser extent) transfusion outcomes, but none have yet linked

Cholesterol is a major and essential component of the mammalian cell plasma membrane (PM), and the loss of cholesterol homeostasis leads to various pathologies. Cellular cholesterol uptake and synthesis are regulated by a cholesterol sensor in the endoplasmic reticulum (ER). However, it remains unclear how changes in the cholesterol level of the PM are recognized. Here we show that the sensing of cholesterol

During prolonged mitotic arrest induced by anti-microtubule drugs, cell fate decision is determined by two alternative pathways, one leading to cell death, the other inducing premature escape from mitosis by mitotic slippage. FBWX7, a member of the F-box family of proteins and substrate-targeting subunit of the SCF (SKP1-CUL1-F-Box) E3 ubiquitin ligase complex promotes mitotic cell death and prevents

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd =0.13 ± 0.02 μM) without inducing heat shock