-
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 -
Nature Structural & Molecular Biology Dec 2023Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR)....
Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation.
Topics: Humans; Receptors, Glucocorticoid; Cryoelectron Microscopy; Tacrolimus Binding Proteins; HSP90 Heat-Shock Proteins; Molecular Chaperones; Protein Binding
PubMed: 37945740
DOI: 10.1038/s41594-023-01128-y -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Nov 2022Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining... (Review)
Review
Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space. Mutations in the essential tremor-associated DNAJC13 gene can prevent endosome protein trafficking. This article reviews the mechanism of DNAJ protein family in neurodegenerative diseases.
Topics: Humans; HSP40 Heat-Shock Proteins; alpha-Synuclein; Neurodegenerative Diseases; Essential Tremor; Protein Folding; Nerve Tissue Proteins; Molecular Chaperones
PubMed: 36581576
DOI: 10.3724/zdxbyxb-2021-0406 -
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 -
Biomolecules Mar 2023The 70 kDa heat shock proteins (HSP70s) are a group of highly conserved and inducible heat shock proteins. One of the main functions of HSP70s is to act as molecular... (Review)
Review
The 70 kDa heat shock proteins (HSP70s) are a group of highly conserved and inducible heat shock proteins. One of the main functions of HSP70s is to act as molecular chaperones that are involved in a large variety of cellular protein folding and remodeling processes. HSP70s are found to be over-expressed and may serve as prognostic markers in many types of cancers. HSP70s are also involved in most of the molecular processes of cancer hallmarks as well as the growth and survival of cancer cells. In fact, many effects of HSP70s on cancer cells are not only related to their chaperone activities but rather to their roles in regulating cancer cell signaling. Therefore, a number of drugs directly or indirectly targeting HSP70s, and their co-chaperones have been developed aiming to treat cancer. In this review, we summarized HSP70-related cancer signaling pathways and corresponding key proteins regulated by the family of HSP70s. In addition, we also summarized various treatment approaches and progress of anti-tumor therapy based on targeting HSP70 family proteins.
Topics: Humans; HSP70 Heat-Shock Proteins; Protein Folding; Heat-Shock Proteins; Molecular Chaperones; Neoplasms; Signal Transduction
PubMed: 37189349
DOI: 10.3390/biom13040601 -
The Journal of Biological Chemistry 2021This review contains a personal account of the role played by the PDB in the development of the field of molecular chaperones and protein homeostasis, from the viewpoint... (Review)
Review
This review contains a personal account of the role played by the PDB in the development of the field of molecular chaperones and protein homeostasis, from the viewpoint of someone who experienced the concurrent advances in the structural biology, electron microscopy, and chaperone fields. The emphasis is on some key structures, including those of Hsp70, GroEL, Hsp90, and small heat shock proteins, that were determined as the molecular chaperone concept and systems for protein quality control were emerging. These structures were pivotal in demonstrating how seemingly nonspecific chaperones could assist the specific folding pathways of a variety of substrates. Moreover, they have provided mechanistic insights into the ATPase machinery of complexes such as GroEL/GroES that promote unfolding and folding and the disaggregases that extract polypeptides from large aggregates and disassemble amyloid fibers. The PDB has provided a framework for the current success in curating, evaluating, and distributing structural biology data, through both the PDB and the EMDB.
Topics: Animals; Chaperonin 10; Chaperonin 60; Databases, Protein; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Proteolysis
PubMed: 33957121
DOI: 10.1016/j.jbc.2021.100744 -
International Journal of Molecular... Feb 2022Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain... (Review)
Review
Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain proteins, which involves multiple steps of segmental folding, is one of the biggest questions in protein science. Multidomain protein folding often requires the assistance of molecular chaperones. Molecular chaperones promote or delay the folding of the client protein, but the detailed mechanisms are still unclear. This review summarizes the findings of biophysical and structural studies on the mechanism of multidomain protein folding mediated by molecular chaperones and explains how molecular chaperones recognize the client proteins and alter their folding properties. Furthermore, we introduce several recent studies that describe the concept of kinetics-activity relationships to explain the mechanism of functional diversity of molecular chaperones.
Topics: Humans; Kinetics; Molecular Chaperones; Protein Folding
PubMed: 35269628
DOI: 10.3390/ijms23052485 -
Protein Science : a Publication of the... Feb 2020As one of the most abundant and highly conserved molecular chaperones, the 70-kDa heat shock proteins (Hsp70s) play a key role in maintaining cellular protein... (Review)
Review
As one of the most abundant and highly conserved molecular chaperones, the 70-kDa heat shock proteins (Hsp70s) play a key role in maintaining cellular protein homeostasis (proteostasis), one of the most fundamental tasks for every living organism. In this role, Hsp70s are inextricably linked to many human diseases, most notably cancers and neurodegenerative diseases, and are increasingly recognized as important drug targets for developing novel therapeutics for these diseases. Hsp40s are a class of essential and universal partners for Hsp70s in almost all aspects of proteostasis. Thus, Hsp70s and Hsp40s together constitute one of the most important chaperone systems across all kingdoms of life. In recent years, we have witnessed significant progress in understanding the molecular mechanism of this chaperone system through structural and functional analysis. This review will focus on this recent progress, mainly from a structural perspective.
Topics: HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 31509306
DOI: 10.1002/pro.3725 -
Cold Spring Harbor Perspectives in... Sep 2019Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the maturation of a plethora of substrates ("clients"), including protein kinases, transcription... (Review)
Review
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the maturation of a plethora of substrates ("clients"), including protein kinases, transcription factors, and E3 ubiquitin ligases, positioning Hsp90 as a central regulator of cellular proteostasis. Hsp90 undergoes large conformational changes during its ATPase cycle. The processing of clients by cytosolic Hsp90 is assisted by a cohort of cochaperones that affect client recruitment, Hsp90 ATPase function or conformational rearrangements in Hsp90. Because of the importance of Hsp90 in regulating central cellular pathways, strategies for the pharmacological inhibition of the Hsp90 machinery in diseases such as cancer and neurodegeneration are being developed. In this review, we summarize recent structural and mechanistic progress in defining the function of organelle-specific and cytosolic Hsp90, including the impact of individual cochaperones on the maturation of specific clients and complexes with clients as well as ways of exploiting Hsp90 as a drug target.
Topics: Adenosine Triphosphatases; Animals; Binding Sites; Cytosol; Databases, Protein; Evolution, Molecular; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Humans; Membrane Glycoproteins; Mental Disorders; Mice; Mitochondria; Molecular Chaperones; Neurodegenerative Diseases; Peptides; Protein Domains; Protein Isoforms; Proteostasis
PubMed: 30745292
DOI: 10.1101/cshperspect.a034017 -
Cell Mar 2023Hsp60 chaperonins and their Hsp10 cofactors assist protein folding in all living cells, constituting the paradigmatic example of molecular chaperones. Despite extensive...
Hsp60 chaperonins and their Hsp10 cofactors assist protein folding in all living cells, constituting the paradigmatic example of molecular chaperones. Despite extensive investigations of their structure and mechanism, crucial questions regarding how these chaperonins promote folding remain unsolved. Here, we report that the bacterial Hsp60 chaperonin GroEL forms a stable, functionally relevant complex with the chaperedoxin CnoX, a protein combining a chaperone and a redox function. Binding of GroES (Hsp10 cofactor) to GroEL induces CnoX release. Cryoelectron microscopy provided crucial structural information on the GroEL-CnoX complex, showing that CnoX binds GroEL outside the substrate-binding site via a highly conserved C-terminal α-helix. Furthermore, we identified complexes in which CnoX, bound to GroEL, forms mixed disulfides with GroEL substrates, indicating that CnoX likely functions as a redox quality-control plugin for GroEL. Proteins sharing structural features with CnoX exist in eukaryotes, suggesting that Hsp60 molecular plugins have been conserved through evolution.
Topics: Cryoelectron Microscopy; Protein Folding; Molecular Chaperones; Oxidation-Reduction; Chaperonins; Chaperonin 60; Chaperonin 10
PubMed: 36764293
DOI: 10.1016/j.cell.2023.01.013