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Nature Structural & Molecular Biology Mar 2015Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42)....
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cryoelectron Microscopy; Electrophysiology; Female; Hippocampus; Humans; Kinetics; Male; Mice; Mice, Inbred C57BL; Molecular Chaperones; Protein Aggregation, Pathological; Protein Folding; Protein Structure, Tertiary
PubMed: 25686087
DOI: 10.1038/nsmb.2971 -
Trends in Biochemical Sciences Jan 2018The Rvb1-Rvb2-Tah1-Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein... (Review)
Review
The Rvb1-Rvb2-Tah1-Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein complexes in mammalian cells. Here, we propose to rename R2TP/PFDL as PAQosome (particle for arrangement of quaternary structure) to more accurately represent its unique function.
Topics: ATPases Associated with Diverse Cellular Activities; Apoptosis Regulatory Proteins; Carrier Proteins; DNA Helicases; Humans; Molecular Chaperones; Multiprotein Complexes; Protein Structure, Quaternary
PubMed: 29203338
DOI: 10.1016/j.tibs.2017.11.001 -
The Journal of Biological Chemistry Aug 2020Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may... (Review)
Review
Cells have a remarkable ability to synthesize large amounts of protein in a very short period of time. Under these conditions, many hydrophobic surfaces on proteins may be transiently exposed, and the likelihood of deleterious interactions is quite high. To counter this threat to cell viability, molecular chaperones have evolved to help nascent polypeptides fold correctly and multimeric protein complexes assemble productively, while minimizing the danger of protein aggregation. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that is involved in the stability and activation of at least 300 proteins, also known as clients, under normal cellular conditions. The Hsp90 clients participate in the full breadth of cellular processes, including cell growth and cell cycle control, signal transduction, DNA repair, transcription, and many others. Hsp90 chaperone function is coupled to its ability to bind and hydrolyze ATP, which is tightly regulated both by co-chaperone proteins and post-translational modifications (PTMs). Many reported PTMs of Hsp90 alter chaperone function and consequently affect myriad cellular processes. Here, we review the contributions of PTMs, such as phosphorylation, acetylation, SUMOylation, methylation, -GlcNAcylation, ubiquitination, and others, toward regulation of Hsp90 function. We also discuss how the Hsp90 modification state affects cellular sensitivity to Hsp90-targeted therapeutics that specifically bind and inhibit its chaperone activity. The ultimate challenge is to decipher the comprehensive and combinatorial array of PTMs that modulate Hsp90 chaperone function, a phenomenon termed the "chaperone code."
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Processing, Post-Translational; Structure-Activity Relationship
PubMed: 32527727
DOI: 10.1074/jbc.REV120.011833 -
Methods in Molecular Biology (Clifton,... 2022The heat shock protein 90 (Hsp90) family of chaperones are well-known, highly important components of the cellular systems which regulate protein homeostasis. Essential...
The heat shock protein 90 (Hsp90) family of chaperones are well-known, highly important components of the cellular systems which regulate protein homeostasis. Essential in eukaryotes, Hsp90s is also found in prokaryotes, including archaea. Hsp90 is a dimeric protein, with each monomer consisting of three separate structural domains, and undergoes large conformational changes as part of its functional cycle. This cycle is driven by interactions with nucleotides, cochaperone proteins, client proteins and allosteric effects enacted by these and by posttranslational modifications. All of these influence the rate and degree of the opening and closing of the dimer as well as the relative domain orientations and its overall rigidity. Optical tweezers, which can access many of these functionally important conformational changes, therefore provide a unique tool for the study of this large and complex molecular chaperone. Here, we provide protocols for the design and implementation of different Hsp90 constructs and optical tweezers experiments for addressing the many open questions about the function of this important molecular chaperone.
Topics: HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Optical Tweezers; Protein Conformation
PubMed: 36063329
DOI: 10.1007/978-1-0716-2229-2_15 -
Journal of Molecular Biology Sep 2015Hsp90 is a molecular chaperone that facilitates the maturation of signaling proteins including many kinases and steroid hormone receptors. Through these client proteins,... (Review)
Review
Hsp90 is a molecular chaperone that facilitates the maturation of signaling proteins including many kinases and steroid hormone receptors. Through these client proteins, Hsp90 is a key mediator of many physiological processes and has emerged as a promising drug target in cancer. Additionally, Hsp90 can mask or potentiate the impact of mutations in clients with remarkable influence on evolutionary adaptations. The influential roles of Hsp90 in biology and disease have stimulated extensive research into the molecular mechanism of this chaperone. These studies have shown that Hsp90 is a homodimeric protein that requires ATP hydrolysis and a host of accessory proteins termed co-chaperones to facilitate the maturation of clients to their active states. Flexible hinge regions between its three structured domains enable Hsp90 to sample dramatically distinct conformations that are influenced by nucleotide, client, and co-chaperone binding. While it is clear that Hsp90 can exist in symmetrical conformations, recent studies have indicated that this homodimeric chaperone can also assume a variety of asymmetric conformations and complexes that are important for client maturation. The visualization of Hsp90-client complexes at high resolution together with tools to independently manipulate each subunit in the Hsp90 dimer are providing new insights into the asymmetric function of each subunit during client maturation.
Topics: Adenosine Triphosphate; HSP90 Heat-Shock Proteins; Humans; Hydrolysis; Molecular Chaperones; Mutation; Nucleotides; Protein Binding; Protein Conformation; Protein Multimerization; Signal Transduction
PubMed: 25843003
DOI: 10.1016/j.jmb.2015.03.017 -
Cell Stress & Chaperones May 2023Hsp90 is a molecular chaperone responsible for regulating proteostasis under physiological and pathological conditions. Its central role in a range of diseases and... (Review)
Review
Hsp90 is a molecular chaperone responsible for regulating proteostasis under physiological and pathological conditions. Its central role in a range of diseases and potential as a drug target has focused efforts to understand its mechanisms and biological functions and to identify modulators that may form the basis for therapies. The 10 international conference on the Hsp90 chaperone machine was held in Switzerland in October 2022. The meeting was organized by Didier Picard (Geneva, Switzerland) and Johannes Buchner (Garching, Germany) with an advisory committee of Olivier Genest, Mehdi Mollapour, Ritwick Sawarkar, and Patricija van Oosten-Hawle. This was a much anticipated first in-person meeting of the Hsp90 community since 2018 after the COVID-19 pandemic led to the postponement of the 2020 meeting. The conference remained true to the tradition of sharing novel data ahead of publication, providing unparalleled depth of insight for both experts and newcomers to the field.
Topics: Humans; Switzerland; Pandemics; Protein Binding; COVID-19; Molecular Chaperones; HSP90 Heat-Shock Proteins
PubMed: 37071341
DOI: 10.1007/s12192-023-01342-z -
Journal of Molecular Biology Sep 2018The molecular chaperone Hsp90 is involved in the folding, maturation, and degradation of a large number structurally and sequentially unrelated clients, often connected... (Review)
Review
The molecular chaperone Hsp90 is involved in the folding, maturation, and degradation of a large number structurally and sequentially unrelated clients, often connected to serious diseases. Elucidating the principles of how Hsp90 recognizes this large variety of substrates is essential for comprehending the mechanism of this chaperone machinery, as well as it is a prerequisite for the design of client specific drugs targeting Hsp90. Here, we discuss the recent progress in understanding the substrate recognition principles of Hsp90 and its implications for the role of Hsp90 in the lifecycle of proteins. Hsp90 acts downstream of the chaperone Hsp70, which exposes its substrate to a short and highly hydrophobic cleft. The subsequently acting Hsp90 has an extended client-binding interface that enables a large number of low-affinity contacts. Structural studies show interaction modes of Hsp90 with the intrinsically disordered Alzheimer's disease-causing protein Tau, the kinase Cdk4 in a partially unfolded state and the folded ligand-binding domain of a steroid receptor. Comparing the features shared by these different proteins provides a picture of the substrate-binding principles of Hsp90.
Topics: Animals; Binding Sites; Carrier Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Chaperones; Protein Binding; Protein Interaction Domains and Motifs; Structure-Activity Relationship
PubMed: 29782836
DOI: 10.1016/j.jmb.2018.05.026 -
Advances in Enzymology and Related... 1994
Review
Topics: Animals; Base Sequence; Crystallins; Drosophila; Gene Expression Regulation; Heat-Shock Proteins; Humans; Lens, Crystalline; Mice; Mice, Transgenic; Molecular Chaperones; Molecular Sequence Data
PubMed: 7817868
DOI: 10.1002/9780470123157.ch5 -
Biomolecules Aug 2022The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two... (Review)
Review
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications.
Topics: Animals; HSP90 Heat-Shock Proteins; Mice; Molecular Chaperones; Protein Isoforms; Proteome
PubMed: 36139005
DOI: 10.3390/biom12091166 -
Histology and Histopathology Nov 2008Glucose-regulated protein 78 (GRP78) is a well-characterized molecular chaperone that is ubiquitously expressed in mammalian cells. GRP78 is best known for binding to... (Review)
Review
Glucose-regulated protein 78 (GRP78) is a well-characterized molecular chaperone that is ubiquitously expressed in mammalian cells. GRP78 is best known for binding to hydrophobic patches on nascent polypeptides within the endoplasmic reticulum (ER) and for its role in signaling the unfolded protein response. Structurally, GRP78 is highly conserved across species. The presence of GRP78 or a homologue in nearly every organism from bacteria to man, reflects the central roles it plays in cell survival. While the principal role of GRP78 as a molecular chaperone is a matter of continuing study, independent work demonstrates that like many other proteins with ancient origins, GRP78 plays more roles than originally appreciated. Studies have shown that GRP78 is expressed on the cell surface in many tissue types both in vitro and in vivo. Cell surface GRP78 is involved in transducing signals from ligands as disparate as activated alpha2-macroglobulin and antibodies. Plasmalemmar GRP78 also plays a role in viral entry of Coxsackie B, and Dengue Fever viruses. GRP78 disregulation is also implicated in atherosclerotic, thrombotic, and auto-immune disease. It is challenging to posit a hypothesis as to why an ER molecular chaperone, such as GRP78, plays such a variety of roles in cellular processes. An ancient and highly conserved protein such as GRP78, whose primary function is to bind to misfolded polypeptides, could be uniquely suited to bind a wide variety of ligands and thus, over time, could assume the wide variety of roles it now plays.
Topics: Animals; Autoimmune Diseases; Cardiovascular Diseases; Cell Membrane; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Inflammation; Ligands; Molecular Chaperones; Neoplasms; Protein Folding; Signal Transduction; Virus Diseases
PubMed: 18785123
DOI: 10.14670/HH-23.1409