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Biomolecules Nov 2022The core-1 β1-3galactosyltransferase-specific chaperone 1 (Cosmc) is a unique molecular chaperone of core-1 β1-3galactosyltransferase(C1GALT1), which typically... (Review)
Review
The core-1 β1-3galactosyltransferase-specific chaperone 1 (Cosmc) is a unique molecular chaperone of core-1 β1-3galactosyltransferase(C1GALT1), which typically functions inside the endoplasmic reticulum (ER). Cosmc helps C1GALT1 to fold correctly and maintain activity. It also participates in the synthesis of the T antigen, O-glycan, together with C1GALT1. Cosmc is a multifaceted molecule with a wide range of roles and functions. It involves platelet production and the regulation of immune cell function. Besides that, the loss of function of Cosmc also facilitates the development of several diseases, such as inflammation diseases, immune-mediated diseases, and cancer. It suggests that Cosmc is a critical control point in diseases and that it should be regarded as a potential target for oncotherapy. It is essential to fully comprehend Cosmc's roles, as they may provide critical information about its involvement in disease development and pathogenesis. In this review, we summarize the recent progress in understanding the role of Cosmc in normal development and diseases.
Topics: Humans; Endoplasmic Reticulum; Molecular Chaperones; Disease; Glycosylation
PubMed: 36551160
DOI: 10.3390/biom12121732 -
Cell Chemical Biology May 2022The molecular chaperone DnaK, is an attractive drug target for treating mycobacterial infections. In this issue, Hosfelt, Richards, and colleagues applied a...
The molecular chaperone DnaK, is an attractive drug target for treating mycobacterial infections. In this issue, Hosfelt, Richards, and colleagues applied a high-throughput screen and discovered inhibitors that disrupt cofactor-mediated activation of DnaK. These inhibitors can lower bacterial survival under stress and decrease resistance to key antibiotics.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Escherichia coli Proteins; HSP70 Heat-Shock Proteins; Molecular Chaperones
PubMed: 35594848
DOI: 10.1016/j.chembiol.2022.05.002 -
Traffic (Copenhagen, Denmark) Apr 2016Helenius and colleagues proposed over 20-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new... (Review)
Review
Helenius and colleagues proposed over 20-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate-binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review.
Topics: Animals; Calnexin; Endoplasmic Reticulum; Humans; Molecular Chaperones; Polysaccharides; Protein Binding; Unfolded Protein Response
PubMed: 26676362
DOI: 10.1111/tra.12358 -
Haematologica Jun 2021Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates.... (Review)
Review
Erythropoiesis is a tightly regulated cell differentiation process in which specialized oxygen- and carbon dioxide-carrying red blood cells are generated in vertebrates. Extensive reorganization and depletion of the erythroblast proteome leading to the deterioration of general cellular protein quality control pathways and rapid hemoglobin biogenesis rates could generate misfolded/aggregated proteins and trigger proteotoxic stresses during erythropoiesis. Such cytotoxic conditions could prevent proper cell differentiation resulting in premature apoptosis of erythroblasts (ineffective erythropoiesis). The heat shock protein 70 (Hsp70) molecular chaperone system supports a plethora of functions that help maintain cellular protein homeostasis (proteostasis) and promote red blood cell differentiation and survival. Recent findings show that abnormalities in the expression, localization and function of the members of this chaperone system are linked to ineffective erythropoiesis in multiple hematological diseases in humans. In this review, we present latest advances in our understanding of the distinct functions of this chaperone system in differentiating erythroblasts and terminally differentiated mature erythrocytes. We present new insights into the protein repair-only function(s) of the Hsp70 system, perhaps to minimize protein degradation in mature erythrocytes to warrant their optimal function and survival in the vasculature under healthy conditions. The work also discusses the modulatory roles of this chaperone system in a wide range of hematological diseases and the therapeutic gain of targeting Hsp70.
Topics: Animals; Erythroblasts; Erythrocytes; Erythropoiesis; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones
PubMed: 33832207
DOI: 10.3324/haematol.2019.233056 -
Biochimica Et Biophysica Acta Nov 2013Extracellular matrix (ECM) proteins create structural frameworks in tissues such as bone, skin, tendon and cartilage etc. These connective tissues play important roles... (Review)
Review
Extracellular matrix (ECM) proteins create structural frameworks in tissues such as bone, skin, tendon and cartilage etc. These connective tissues play important roles in the development and homeostasis of organs. Collagen is the most abundant ECM protein and represents one third of all proteins in humans. The biosynthesis of ECM proteins occurs in the rough endoplasmic reticulum (rER). This review describes the current understanding of the biosynthesis and folding of procollagens, which are the precursor molecules of collagens, in the rER. Multiple folding enzymes and molecular chaperones are required for procollagen to establish specific posttranslational modifications, and facilitate folding and transport to the cell surface. Thus, this molecular ensemble in the rER contributes to ECM maturation and to the development and homeostasis of tissues. Mutations in this ensemble are likely candidates for connective tissue disorders. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Topics: Animals; Endoplasmic Reticulum, Rough; Extracellular Matrix Proteins; Humans; Molecular Chaperones; Procollagen
PubMed: 23602968
DOI: 10.1016/j.bbamcr.2013.04.008 -
Biochimica Et Biophysica Acta.... Jun 2024Among the six known iron‑sulfur (FeS) cluster biogenesis machineries that function across all domains of life only one involves a molecular chaperone system. This... (Review)
Review
Among the six known iron‑sulfur (FeS) cluster biogenesis machineries that function across all domains of life only one involves a molecular chaperone system. This machinery, called ISC for 'iron sulfur cluster', functions in bacteria and in mitochondria of eukaryotes including humans. The chaperone system - a dedicated J-domain protein co-chaperone termed Hsc20 and its Hsp70 partner - is essential for proper ISC machinery function, interacting with the scaffold protein IscU which serves as a platform for cluster assembly and subsequent transfer onto recipient apo-proteins. Despite many years of research, surprisingly little is known about the specific role(s) that the chaperones play in the ISC machinery. Here we review three non-exclusive scenarios that range from involvement of the chaperones in the cluster transfer to regulation of the cellular levels of IscU itself.
Topics: Iron-Sulfur Proteins; Humans; Molecular Chaperones; HSP70 Heat-Shock Proteins; Mitochondria; Escherichia coli Proteins
PubMed: 38574821
DOI: 10.1016/j.bbamcr.2024.119717 -
Biochimica Et Biophysica Acta Mar 2012Heat shock protein 90 (HSP90) is a highly conserved and essential molecular chaperone involved in maturation and activation of signaling proteins in eukaryotes. HSP90... (Review)
Review
Heat shock protein 90 (HSP90) is a highly conserved and essential molecular chaperone involved in maturation and activation of signaling proteins in eukaryotes. HSP90 operates as a dimer in a conformational cycle driven by ATP binding and hydrolysis. HSP90 often functions together with co-chaperones that regulate the conformational cycle and/or load a substrate "client" protein onto HSP90. In plants, immune sensing NLR (nucleotide-binding domain and leucine-rich repeat containing) proteins are among the few known client proteins of HSP90. In the process of chaperoning NLR proteins, co-chaperones, RAR1 and SGT1 function together with HSP90. Recent structural and functional analyses indicate that RAR1 dynamically controls conformational changes of the HSP90 dimer, allowing SGT1 to bridge the interaction between NLR proteins and HSP90. Here, we discuss the regulation of NLR proteins by HSP90 upon interaction with RAR1 and SGT1, emphasizing the recent progress in our understanding of the structure and function of the complex. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
Topics: HSP90 Heat-Shock Proteins; Models, Molecular; Molecular Chaperones; Plant Proteins; Plants; Structure-Activity Relationship
PubMed: 22001401
DOI: 10.1016/j.bbamcr.2011.09.016 -
Journal of Biomolecular NMR Jan 2021Advanced NMR methods combined with biophysical techniques have recently provided unprecedented insight into structure and dynamics of molecular chaperones and their...
Advanced NMR methods combined with biophysical techniques have recently provided unprecedented insight into structure and dynamics of molecular chaperones and their interaction with client proteins. These studies showed that several molecular chaperones are able to dissolve aggregation-prone polypeptides in aqueous solution. Furthermore, chaperone-bound clients often feature fluid-like backbone dynamics and chaperones have a denaturing effect on clients. Interestingly, these effects that chaperones have on client proteins resemble the effects of known chaotropic substances. Following this analogy, chaotropicity could be a fruitful concept to describe, quantify and rationalize molecular chaperone function. In addition, the observations raise the possibility that at least some molecular chaperones might share functional similarities with chaotropes. We discuss these concepts and outline future research in this direction.
Topics: Humans; Models, Molecular; Molecular Chaperones; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Conformation; Protein Denaturation; Protein Folding; Protein Unfolding; Proteins; Solubility; Structure-Activity Relationship
PubMed: 33136251
DOI: 10.1007/s10858-020-00353-7 -
Methods in Molecular Biology (Clifton,... 2023The molecular chaperone heat shock protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis....
The molecular chaperone heat shock protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis. There are multiple Hsp90 isoforms including the cytosolic Hsp90α and Hsp90β as well as GRP94 located in the endoplasmic reticulum and TRAP1 in the mitochondria. The chaperone function of Hsp90 is linked to its ability to bind and hydrolyze ATP. Co-chaperones and posttranslational modifications (such as phosphorylation, SUMOylation, and ubiquitination) are important for Hsp90 stability and regulation of its ATPase activity. Both mammalian and yeast cells can be used to express and purify Hsp90 and TRAP1 and also detect post-translational modifications by immunoblotting.
Topics: Animals; HSP90 Heat-Shock Proteins; Protein Processing, Post-Translational; Molecular Chaperones; Phosphorylation; Protein Isoforms; Ubiquitination; Saccharomyces cerevisiae; Mammals
PubMed: 37540432
DOI: 10.1007/978-1-0716-3342-7_11 -
Cellular and Molecular Life Sciences :... Feb 2015Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein... (Review)
Review
Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of post-translational modifications in sHsp chaperone function, particularly in the context of disease.
Topics: Heat-Shock Proteins; Homeostasis; Humans; Models, Biological; Models, Molecular; Molecular Chaperones; Multiple Sclerosis; Neoplasms; Neurodegenerative Diseases; Phosphorylation; Polymerization; Protein Aggregation, Pathological; Protein Processing, Post-Translational; alpha-Crystallins
PubMed: 25352169
DOI: 10.1007/s00018-014-1754-5