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Nature Reviews. Molecular Cell Biology Jun 2017The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has... (Review)
Review
The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
Topics: Adenosine Triphosphatases; Animals; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Binding; Protein Folding
PubMed: 28429788
DOI: 10.1038/nrm.2017.20 -
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 -
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 -
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 -
Sub-cellular Biochemistry 2019The crystallins (α, β and γ), major constituent proteins of eye lens fiber cells play their critical role in maintaining the transparency and refractive index of the... (Review)
Review
The crystallins (α, β and γ), major constituent proteins of eye lens fiber cells play their critical role in maintaining the transparency and refractive index of the lens. Under different stress factors and with aging, β- and γ-crystallins start to unfold partially leading to their aggregation. Protein aggregation in lens basically enhances light scattering and causes the vision problem, commonly known as cataract. α-crystallin as a molecular chaperone forms complexes with its substrates (β- and γ-crystallins) to prevent such aggregation. In this chapter, the structural features of β- and γ-crystallins have been discussed. Detailed structural information linked with the high stability of γC-, γD- and γS-crystallins have been incorporated. The nature of homologous and heterologous interactions among crystallins has been deciphered, which are involved in their molecular association and complex formation.
Topics: Cataract; Crystallins; Humans; Lens, Crystalline; Molecular Chaperones; Multiprotein Complexes
PubMed: 31939160
DOI: 10.1007/978-3-030-28151-9_14 -
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 -
Advances in Protein Chemistry and... 2019Defects in protein folding and trafficking are a common cause of photoreceptor degeneration, causing blindness. Photoreceptor cells present an unusual challenge to the... (Review)
Review
Defects in protein folding and trafficking are a common cause of photoreceptor degeneration, causing blindness. Photoreceptor cells present an unusual challenge to the protein folding and transport machinery due to the high rate of protein synthesis, trafficking and the renewal of the outer segment, a primary cilium that has been modified into a specialized light-sensing compartment. Phototransduction components, such as rhodopsin and cGMP-phosphodiesterase, and multimeric ciliary transport complexes, such as the BBSome, are hotspots for mutations that disrupt proteostasis and lead to the death of photoreceptors. In this chapter, we review recent studies that advance our understanding of the chaperone and transport machinery of phototransduction proteins.
Topics: Animals; Humans; Light Signal Transduction; Models, Molecular; Molecular Chaperones; Protein Folding; Retinal Diseases
PubMed: 30635087
DOI: 10.1016/bs.apcsb.2018.09.001 -
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 -
The Enzymes 2023Proteins are the most structurally diverse cellular biomolecules that act as molecular machines driving essential activities of all living organisms. To be functional,... (Review)
Review
Proteins are the most structurally diverse cellular biomolecules that act as molecular machines driving essential activities of all living organisms. To be functional, most of the proteins need to fold into a specific three-dimensional structure, which on one hand should be stable enough to oppose disruptive conditions and on the other hand flexible enough to allow conformational dynamics necessary for their biological functions. This compromise between stability and dynamics makes proteins susceptible to stress-induced misfolding and aggregation. Moreover, the folding process itself is intrinsically prone to conformational errors. Molecular chaperones are proteins that mitigate folding defects and maintain the structural integrity of the cellular proteome. Promiscuous Hsp70 chaperones are central to these processes and their activity depends on the interaction with obligatory J-domain protein (JDP) partners. In this review, we discuss structural aspects of Hsp70s, JDPs, and their interaction in the context of biological activities.
Topics: HSP70 Heat-Shock Proteins; Molecular Chaperones; Humans
PubMed: 37945173
DOI: 10.1016/bs.enz.2023.07.008 -
Sub-cellular Biochemistry 2015Hsp90 is a conserved molecular chaperone and is responsible for the folding and activation of several hundred client proteins, involved in various cellular processes.... (Review)
Review
Hsp90 is a conserved molecular chaperone and is responsible for the folding and activation of several hundred client proteins, involved in various cellular processes. The large number and the diversity of these client proteins demand a high adaptiveness of Hsp90 towards the need of the individual client. This adaptiveness is amongst others mediated by more than 20 so-called cochaperones that differ in their actions towards Hsp90. Some of these cochaperones are able to modulate the ATPase activity of Hsp90 and/or its client protein binding, folding and activation. p23 and Aha1 are two prominent examples with opposing effects on the ATPase activity of Hsp90. p23 is able to inhibit the ATP turnover while Aha1 is the strongest known activator of the ATPase activity of Hsp90. Even though both cochaperones are conserved from yeast to man and have been studied for years, some Hsp90-related as well as Hsp90-independent functions are still enigmatic and under current investigation. In this chapter, we first introduce the ATPase cycle of Hsp90 and then focus on the two cochaperones integrating them in the Hsp90 cycle.
Topics: Animals; HSP90 Heat-Shock Proteins; Humans; Intramolecular Oxidoreductases; Models, Molecular; Molecular Chaperones; Prostaglandin-E Synthases; Protein Conformation; Protein Folding; Signal Transduction; Structure-Activity Relationship
PubMed: 25487019
DOI: 10.1007/978-3-319-11731-7_6