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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 -
BioEssays : News and Reviews in... Nov 2012Molecular chaperones assist de novo protein folding and facilitate the refolding of stress-denatured proteins. The molecular chaperone concept was coined nearly 35 years... (Review)
Review
Molecular chaperones assist de novo protein folding and facilitate the refolding of stress-denatured proteins. The molecular chaperone concept was coined nearly 35 years ago, and since then, tremendous strides have been made in understanding how these factors support protein folding. Here, we focus on how various chaperone proteins were first identified to play roles in protein folding. Examples are used to illustrate traditional routes of chaperone discovery and point out their advantages and limitations. Recent advances, including the development of folding biosensors and promising methods for the stabilization of proteins in vivo, provide new routes for chaperone discovery.
Topics: Animals; Biochemistry; Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Folding
PubMed: 22968800
DOI: 10.1002/bies.201200059 -
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 -
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 -
Biochemical Society Transactions Aug 2020The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational... (Review)
Review
The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.
Topics: Animals; Copper; Heat-Shock Proteins; Humans; Macrophage Migration-Inhibitory Factors; Molecular Chaperones; Mutation; Protein Folding; Superoxide Dismutase-1
PubMed: 32794552
DOI: 10.1042/BST20200318 -
Genes Aug 2022The J-proteins, also called DNAJ-proteins or heat shock protein 40 (HSP40), are one of the famous molecular chaperones. J-proteins, HSP70s and other chaperones work... (Review)
Review
The J-proteins, also called DNAJ-proteins or heat shock protein 40 (HSP40), are one of the famous molecular chaperones. J-proteins, HSP70s and other chaperones work together as constitute ubiquitous types of molecular chaperone complex, which function in a wide variety of physiological processes. J-proteins are widely distributed in major cellular compartments. In the chloroplast of higher plants, around 18 J-proteins and multiple J-like proteins are present; however, the functions of most of them remain unclear. During the last few years, important progress has been made in the research on their roles in plants. There is increasing evidence that the chloroplast J-proteins play essential roles in chloroplast development, photosynthesis, seed germination and stress response. Here, we summarize recent research advances on the roles of J-proteins in the chloroplast, and discuss the open questions that remain in this field.
Topics: Chloroplast Proteins; Chloroplasts; HSP70 Heat-Shock Proteins; Molecular Chaperones; Plants
PubMed: 36011380
DOI: 10.3390/genes13081469 -
Cells Aug 2022Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various... (Review)
Review
Assuring a healthy proteome is indispensable for survival and organismal health. Proteome disbalance and the loss of the proteostasis buffer are hallmarks of various diseases. The essential molecular chaperone Hsp90 is a regulator of the heat shock response via HSF1 and a stabilizer of a plethora of signaling proteins. In this review, we summarize the role of Hsp90 in the cellular and organismal regulation of proteome maintenance.
Topics: HSP90 Heat-Shock Proteins; Heat-Shock Response; Molecular Chaperones; Proteome; Proteostasis
PubMed: 36010556
DOI: 10.3390/cells11162479 -
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 -
Cold Spring Harbor Perspectives in... Oct 2019Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis... (Review)
Review
Maintenance of a healthy and functional proteome in all cellular compartments is critical to cell and organismal homeostasis. Yet, our understanding of the proteostasis process within the nucleus is limited. Here, we discuss the identified roles of the major molecular chaperones Hsp90, Hsp70, and Hsp60 with client proteins working in diverse DNA-associated pathways. The unique challenges facing proteins in the nucleus are considered as well as the conserved features of the molecular chaperone system in facilitating DNA-linked processes. As nuclear protein inclusions are a common feature of protein-aggregation diseases (e.g., neurodegeneration), a better understanding of nuclear proteostasis is warranted.
Topics: Cell Nucleus; DNA; Humans; Molecular Chaperones; Nuclear Proteins
PubMed: 30745291
DOI: 10.1101/cshperspect.a034009 -
Seminars in Cell & Developmental Biology Apr 2015Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an... (Review)
Review
Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.
Topics: Animals; Heat-Shock Proteins; Humans; Molecular Chaperones; Neurodegenerative Diseases; Protein Aggregation, Pathological; Proteins
PubMed: 25770416
DOI: 10.1016/j.semcdb.2015.03.003