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Current Protocols Nov 2022Heat-shock proteins (HSPs), or stress proteins, are abundant and highly conserved, present in all organisms and in all cells. Selected HSPs, also known as chaperones,...
Heat-shock proteins (HSPs), or stress proteins, are abundant and highly conserved, present in all organisms and in all cells. Selected HSPs, also known as chaperones, play crucial roles in folding and unfolding of proteins, assembly of multiprotein complexes, transport and sorting of proteins into correct subcellular compartments, cell-cycle control and signaling, and protection of cells against stress and apoptosis. More recently, HSPs have been shown to be key players in immune responses: during antigen presentation as well as cross-priming, they chaperone and transfer antigenic peptides to class I and class II molecules of the major histocompatibility complexes. In addition, extracellular HSPs can stimulate and cause maturation of professional antigen-presenting cells of the immune system, such as macrophages and dendritic cells. They also chaperone several toll-like receptors, which play a central role in innate immune responses. HSPs constitute a large family of proteins that are often classified based on their molecular weight as Hsp10, Hsp40, Hsp60, Hsp70, Hsp90, etc. This unit contains a table that lists common HSPs and summarizes their characteristics including (a) name, (b) subcellular localization, (c) known function, (d) chromosome assignment, (e) brief comments, and (f) references. © 2022 Wiley Periodicals LLC.
Topics: Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Antigen Presentation; Molecular Chaperones; Antigen-Presenting Cells
PubMed: 36367390
DOI: 10.1002/cpz1.592 -
International Journal of Molecular... Sep 2021HSP90 is a vital chaperone protein conserved across all organisms. As a chaperone protein, it correctly folds client proteins. Structurally, this protein is a dimer with... (Review)
Review
HSP90 is a vital chaperone protein conserved across all organisms. As a chaperone protein, it correctly folds client proteins. Structurally, this protein is a dimer with monomer subunits that consist of three main conserved domains known as the N-terminal domain, middle domain, and the C-terminal domain. Multiple isoforms of HSP90 exist, and these isoforms share high homology. These isoforms are present both within the cell and outside the cell. Isoforms HSP90 and HSP90 are present in the cytoplasm; TRAP1 is present in the mitochondria; and GRP94 is present in the endoplasmic reticulum and is likely secreted due to post-translational modifications (PTM). HSP90 is also secreted into an extracellular environment via an exosome pathway that differs from the classic secretion pathway. Various co-chaperones are necessary for HSP90 to function. Elevated levels of HSP90 have been observed in patients with cancer. Despite this observation, the possible role of HSP90 in cancer was overlooked because the chaperone was also present in extreme amounts in normal cells and was vital to normal cell function, as observed when the drastic adverse effects resulting from gene knockout inhibited the production of this protein. Differences between normal HSP90 and HSP90 of the tumor phenotype have been better understood and have aided in making the chaperone protein a target for cancer drugs. One difference is in the conformation: HSP90 of the tumor phenotype is more susceptible to inhibitors. Since overexpression of HSP90 is a factor in tumorigenesis, HSP90 inhibitors have been studied to combat the adverse effects of HSP90 overexpression. Monotherapies using HSP90 inhibitors have shown some success; however, combination therapies have shown better results and are thus being studied for a more effective cancer treatment.
Topics: Animals; Carcinogenesis; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Neoplasms; Protein Isoforms
PubMed: 34638658
DOI: 10.3390/ijms221910317 -
Nature Jan 2022Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a...
Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p23. However, a molecular understanding of the chaperone-mediated remodelling that occurs between the inactive Hsp70-Hsp90 'client-loading complex' and an activated Hsp90-p23 'client-maturation complex' is lacking for any client, including GR. Here we present a cryo-electron microscopy (cryo-EM) structure of the human GR-maturation complex (GR-Hsp90-p23), revealing that the GR ligand-binding domain is restored to a folded, ligand-bound conformation, while being simultaneously threaded through the Hsp90 lumen. In addition, p23 directly stabilizes native GR using a C-terminal helix, resulting in enhanced ligand binding. This structure of a client bound to Hsp90 in a native conformation contrasts sharply with the unfolded kinase-Hsp90 structure. Thus, aided by direct co-chaperone-client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.
Topics: Cryoelectron Microscopy; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Ligands; Molecular Chaperones; Prostaglandin-E Synthases; Protein Binding; Receptors, Glucocorticoid
PubMed: 34937936
DOI: 10.1038/s41586-021-04236-1 -
Cell Death & Disease Nov 2022Heat shock protein (HSP) 90, an important component of the molecular chaperone network, is closely concerned with cellular signaling pathways and stress response by... (Review)
Review
Heat shock protein (HSP) 90, an important component of the molecular chaperone network, is closely concerned with cellular signaling pathways and stress response by participating in the process of maturation and activation of client proteins, playing a crucial role both in the normal and abnormal operation of the organism. In functionally defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by HSP90, including apoptosis, autophagy, necroptosis, ferroptosis, and others. Here, we show the complex relationship between HSP90 and different types of PCD in various diseases, and discuss the possibility of HSP90 as the common regulatory nodal in multiple PCD, which would provide a new perspective for the therapeutic approaches in disease.
Topics: Humans; HSP90 Heat-Shock Proteins; Apoptosis; Molecular Chaperones; Autophagy
PubMed: 36335088
DOI: 10.1038/s41419-022-05373-9 -
Molecular Cell May 2023Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and...
Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and dysfunctional ribosomes degraded both during assembly, as well as the functional cycle. Oxidative stress downregulates translation and damages mRNAs and ribosomal proteins (RPs). Although damaged mRNAs are detected and degraded via RQC, how cells mitigate damage to RPs is not known. Here, we show that cysteines in Rps26 and Rpl10 are readily oxidized, rendering the proteins non-functional. Oxidized Rps26 and Rpl10 are released from ribosomes by their chaperones, Tsr2 and Sqt1, and the damaged ribosomes are subsequently repaired with newly made proteins. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal an unanticipated mechanism for chaperone-mediated ribosome repair, augment our understanding of ribosome quality control, and explain previous observations of protein exchange in ribosomes from dendrites, with broad implications for aging and health.
Topics: Ribosomes; Ribosomal Proteins; Molecular Chaperones; Oxidative Stress; Protein Biosynthesis
PubMed: 37086725
DOI: 10.1016/j.molcel.2023.03.030 -
The Hsp90 molecular chaperone governs client proteins by targeting intrinsically disordered regions.Molecular Cell Jun 2023Molecular chaperones govern proteome health to support cell homeostasis. An essential eukaryotic component of the chaperone system is Hsp90. Using a chemical-biology...
Molecular chaperones govern proteome health to support cell homeostasis. An essential eukaryotic component of the chaperone system is Hsp90. Using a chemical-biology approach, we characterized the features driving the Hsp90 physical interactome. We found that Hsp90 associated with ∼20% of the yeast proteome using its three domains to preferentially target intrinsically disordered regions (IDRs) of client proteins. Hsp90 selectively utilized an IDR to regulate client activity as well as maintained IDR-protein health by preventing the transition to stress granules or P-bodies at physiological temperatures. We also discovered that Hsp90 controls the fidelity of ribosome initiation that triggers a heat shock response when disrupted. Our study provides insights into how this abundant molecular chaperone supports a dynamic and healthy native protein landscape.
Topics: Humans; HSP90 Heat-Shock Proteins; Molecular Chaperones; Proteome; Saccharomyces cerevisiae; Intrinsically Disordered Proteins
PubMed: 37295430
DOI: 10.1016/j.molcel.2023.05.021 -
Molecular Cell Apr 2023A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone...
A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using exploratory interactomics, we define the interplay between human histone H3-H4 chaperones in the histone chaperone network. We identify previously uncharacterized histone-dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3-H4 prior to deposition onto DNA. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states.
Topics: Humans; Histones; Histone Chaperones; Nucleosomes; Cell Cycle Proteins; DNA; Molecular Chaperones; Co-Repressor Proteins
PubMed: 36868228
DOI: 10.1016/j.molcel.2023.02.009 -
Cells Jan 2023Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein with an N-terminal domain that resides in the lumen of the ER and a C-terminal domain that... (Review)
Review
Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein with an N-terminal domain that resides in the lumen of the ER and a C-terminal domain that extends into the cytosol. Calnexin is commonly referred to as a molecular chaperone involved in the folding and quality control of membrane-associated and secreted proteins, a function that is attributed to its ER- localized domain with a structure that bears a strong resemblance to another luminal ER chaperone and Ca-binding protein known as calreticulin. Studies have discovered that the cytosolic C-terminal domain of calnexin undergoes distinct post-translational modifications and interacts with a variety of proteins. Here, we discuss recent findings and hypothesize that the post-translational modifications of the calnexin C-terminal domain and its interaction with specific cytosolic proteins play a role in coordinating ER functions with events taking place in the cytosol and other cellular compartments.
Topics: Calnexin; Molecular Chaperones; Endoplasmic Reticulum; Membrane Proteins; Cytosol
PubMed: 36766745
DOI: 10.3390/cells12030403 -
Biomolecules Jan 2023Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction.... (Review)
Review
Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals.
Topics: Humans; Animals; HSP90 Heat-Shock Proteins; Molecular Chaperones; Signal Transduction; Proteostasis; Stress, Physiological; Mammals
PubMed: 36830620
DOI: 10.3390/biom13020251 -
International Journal of Molecular... Apr 2022Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3,... (Review)
Review
Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin-proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.
Topics: Amyotrophic Lateral Sclerosis; Heat-Shock Proteins; Humans; Molecular Chaperones; Mutation; Protein Folding; Superoxide Dismutase-1
PubMed: 35456894
DOI: 10.3390/ijms23084076