Mechanisms of Protein Quality Control in the Endoplasmic Reticulum by a Coordinated Hsp40-Hsp70-Hsp90 System.

The Hsp40, Hsp70, and Hsp90 chaperone families are ancient, highly conserved, and critical to cellular protein homeostasis. Hsp40 chaperones can transfer their protein clients to Hsp70, and Hsp70 can transfer clients to Hsp90, but the functional benefits of these transfers are unclear. Recent structural and mechanistic work has opened up the possibility of uncovering how Hsp40, Hsp70, and Hsp90 work together as unified system. In this review, we compile mechanistic data on the ER J-domain protein 3 (ERdj3) (an Hsp40), BiP (an Hsp70), and Grp94 (an Hsp90) chaperones within the endoplasmic reticulum; what is known about how these chaperones work together; and gaps in this understanding. Using calculations, we examine how client transfer could impact the solubilization of aggregates, the folding of soluble proteins, and the triage decisions by which proteins are targeted for degradation. The proposed roles of client transfer among Hsp40-Hsp70-Hsp90 chaperones are new hypotheses, and we discuss potential experimental tests of these ideas.

[1]  Andrea N. Kravats,et al.  Grp94 works upstream of BiP in protein remodeling under heat stress. , 2022, Journal of molecular biology.

[2]  Timothy O. Street,et al.  Electrostatics drive the molecular chaperone BiP to preferentially bind oligomerized states of a client protein. , 2022, Journal of molecular biology.

[3]  J. Gelles,et al.  The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94 , 2022, Proceedings of the National Academy of Sciences.

[4]  K. Zak,et al.  NudC guides client transfer between the Hsp40/70 and Hsp90 chaperone systems. , 2022, Molecular cell.

[5]  D. Agard,et al.  Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism , 2021, Nature.

[6]  D. Agard,et al.  Structure of Hsp90–Hsp70–Hop–GR reveals the Hsp90 client-loading mechanism , 2021, Nature.

[7]  J. Halpin,et al.  The ER chaperones BiP and Grp94 regulate the formation of insulin-like growth factor 2 (IGF2) oligomers. , 2021, Journal of molecular biology.

[8]  M. Varjosalo,et al.  The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor , 2021, The Journal of biological chemistry.

[9]  Y. Argon,et al.  Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production , 2020, Cells.

[10]  G. Hummer,et al.  Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex , 2020, Science.

[11]  T. Waigh,et al.  Network organisation and the dynamics of tubules in the endoplasmic reticulum , 2020, Scientific Reports.

[12]  L. Hendershot,et al.  Disposing of misfolded ER proteins: A troubled substrate's way out of the ER , 2020, Molecular and Cellular Endocrinology.

[13]  C. Kalodimos,et al.  Structural basis for client recognition and activity of Hsp40 chaperones , 2019, Science.

[14]  J. Gelles,et al.  Conformational Cycling within the Closed State of Grp94, an Hsp90-Family Chaperone. , 2019, Journal of molecular biology.

[15]  D. Ron,et al.  MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP , 2019, Nature Communications.

[16]  M. Mayer,et al.  The Hsp70-Hsp90 Chaperone Cascade in Protein Folding. , 2019, Trends in cell biology.

[17]  Roman Kityk,et al.  Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System. , 2018, Molecular cell.

[18]  T. Rapoport,et al.  Mechanistic insights into ER-associated protein degradation. , 2018, Current opinion in cell biology.

[19]  A. Ciechanover,et al.  The endoplasmic reticulum–residing chaperone BiP is short-lived and metabolized through N-terminal arginylation , 2018, Science Signaling.

[20]  Roman Kityk,et al.  Molecular Mechanism of J-Domain-Triggered ATP Hydrolysis by Hsp70 Chaperones. , 2017, Molecular cell.

[21]  T. Waigh,et al.  The flexibility and dynamics of the tubules in the endoplasmic reticulum , 2017, Scientific Reports.

[22]  Qinglian Liu,et al.  Conformation transitions of the polypeptide-binding pocket support an active substrate release from Hsp70s , 2017, Nature Communications.

[23]  Zihai Li,et al.  Structural and Functional Analysis of GRP94 in the Closed State Reveals an Essential Role for the Pre-N Domain and a Potential Client-Binding Site. , 2017, Cell reports.

[24]  Daniel W. Farrell,et al.  Bacterial proteostasis balances energy and chaperone utilization efficiently , 2017, Proceedings of the National Academy of Sciences.

[25]  S. Larson,et al.  The epichaperome is an integrated chaperome network that facilitates tumour survival , 2016, Nature.

[26]  Matthias J. Feige,et al.  Members of the Hsp70 Family Recognize Distinct Types of Sequences to Execute ER Quality Control. , 2016, Molecular cell.

[27]  R. Gilmore,et al.  N-linked glycosylation and homeostasis of the endoplasmic reticulum. , 2016, Current opinion in cell biology.

[28]  D. Agard,et al.  Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase , 2016, Science.

[29]  Qinglian Liu,et al.  Close and Allosteric Opening of the Polypeptide-Binding Site in a Human Hsp70 Chaperone BiP. , 2015, Structure.

[30]  S. Rüdiger,et al.  Hsp90 interaction with clients. , 2015, Trends in biochemical sciences.

[31]  T. Gidalevitz,et al.  Orchestration of secretory protein folding by ER chaperones. , 2013, Biochimica et biophysica acta.

[32]  B. Bukau,et al.  Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation , 2012, The Journal of cell biology.

[33]  L. Gierasch,et al.  FoldEco: a model for proteostasis in E. coli. , 2012, Cell reports.

[34]  A. Hoenger,et al.  A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature , 2011, The Journal of cell biology.

[35]  Matthias J. Feige,et al.  Substrate discrimination of the chaperone BiP by autonomous and cochaperone-regulated conformational transitions , 2011, Nature Structural &Molecular Biology.

[36]  B. Hao,et al.  Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone , 2010, Nature communications.

[37]  V. Rybin,et al.  CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70‐bound substrates , 2010, The FEBS journal.

[38]  A. Rhie,et al.  The binding of the molecular chaperone Hsc70 to the prion protein PrP is modulated by pH and copper. , 2010, The international journal of biochemistry & cell biology.

[39]  E. Snapp,et al.  BiP Availability Distinguishes States of Homeostasis and Stress in the Endoplasmic Reticulum of Living Cells , 2010, Molecular biology of the cell.

[40]  Johannes Buchner,et al.  How antibodies fold. , 2010, Trends in biochemical sciences.

[41]  David Eisenberg,et al.  In Brief , 2009, Nature Reviews Neuroscience.

[42]  Matthias J. Feige,et al.  An unfolded CH1 domain controls the assembly and secretion of IgG antibodies. , 2009, Molecular cell.

[43]  Peter M. Douglas,et al.  Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones. , 2009, Trends in biochemical sciences.

[44]  Jens Schneider-Mergener,et al.  Molecular basis for regulation of the heat shock transcription factor sigma32 by the DnaK and DnaJ chaperones. , 2008, Molecular cell.

[45]  Hiderou Yoshida,et al.  Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. , 2007, Developmental cell.

[46]  G. Blatch,et al.  Not all J domains are created equal: Implications for the specificity of Hsp40–Hsp70 interactions , 2005, Protein science : a publication of the Protein Society.

[47]  L. Hendershot,et al.  ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. , 2004, Molecular biology of the cell.

[48]  M. Galigniana,et al.  Role of molecular chaperones in steroid receptor action. , 2004, Essays in biochemistry.

[49]  L. Hendershot,et al.  A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. , 2002, Molecular biology of the cell.

[50]  J. Reinstein,et al.  GrpE accelerates nucleotide exchange of the molecular chaperone DnaK with an associative displacement mechanism. , 1997, Biochemistry.

[51]  J. Kearney,et al.  Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain-binding protein , 1987, The Journal of cell biology.