The Known Unknowns of the Hsp90 Chaperone

Overview

Journal Elife

Specialty Biology

Date 2024 Dec 31

PMID 39737863

Authors

Laura-Marie Silbermann

Benjamin Vermeer

Sonja Schmid

Katarzyna Tych

Affiliations

Soon will be listed here.

Abstract

Molecular chaperones are vital proteins that maintain protein homeostasis by assisting in protein folding, activation, degradation, and stress protection. Among them, heat-shock protein 90 (Hsp90) stands out as an essential proteostasis hub in eukaryotes, chaperoning hundreds of 'clients' (substrates). After decades of research, several 'known unknowns' about the molecular function of Hsp90 remain unanswered, hampering rational drug design for the treatment of cancers, neurodegenerative, and other diseases. We highlight three fundamental open questions, reviewing the current state of the field for each, and discuss new opportunities, including single-molecule technologies, to answer the known unknowns of the Hsp90 chaperone.

References

Keramisanou D, Aboalroub A, Zhang Z, Liu W, Marshall D, Diviney A . Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37. Mol Cell. 2016; 62(2):260-271. PMC: 4868553. DOI: 10.1016/j.molcel.2016.04.005. View

Richter K, Walter S, Buchner J . The Co-chaperone Sba1 connects the ATPase reaction of Hsp90 to the progression of the chaperone cycle. J Mol Biol. 2004; 342(5):1403-13. DOI: 10.1016/j.jmb.2004.07.064. View

Tych K, Jahn M, Gegenfurtner F, Hechtl V, Buchner J, Hugel T . Nucleotide-Dependent Dimer Association and Dissociation of the Chaperone Hsp90. J Phys Chem B. 2018; 122(49):11373-11380. DOI: 10.1021/acs.jpcb.8b07301. View

Jahn M, Buchner J, Hugel T, Rief M . Folding and assembly of the large molecular machine Hsp90 studied in single-molecule experiments. Proc Natl Acad Sci U S A. 2016; 113(5):1232-7. PMC: 4747692. DOI: 10.1073/pnas.1518827113. View

Lorenz O, Freiburger L, Rutz D, Krause M, Zierer B, Alvira S . Modulation of the Hsp90 chaperone cycle by a stringent client protein. Mol Cell. 2014; 53(6):941-53. DOI: 10.1016/j.molcel.2014.02.003. View

Radli M, Rudiger S . Picky Hsp90-Every Game with Another Mate. Mol Cell. 2017; 67(6):899-900. DOI: 10.1016/j.molcel.2017.09.013. View

Shiau A, Harris S, Southworth D, Agard D . Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell. 2006; 127(2):329-40. DOI: 10.1016/j.cell.2006.09.027. View

Rani K, Gotmare A, Maier A, Menghal R, Akhtar N, Fangaria N . Identification of a chaperone-code responsible for Rad51-mediated genome repair. J Biol Chem. 2024; 300(6):107342. PMC: 11154708. DOI: 10.1016/j.jbc.2024.107342. View

Wolf S, Sohmen B, Hellenkamp B, Thurn J, Stock G, Hugel T . Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations. Chem Sci. 2021; 12(9):3350-3359. PMC: 8179424. DOI: 10.1039/d0sc06134d. View

10.

Mondol T, Silbermann L, Schimpf J, Vollmar L, Hermann B, Tych K . Aha1 regulates Hsp90's conformation and function in a stoichiometry-dependent way. Biophys J. 2023; 122(17):3458-3468. PMC: 10502475. DOI: 10.1016/j.bpj.2023.07.020. View

11.

Manjarrez J, Sun L, Prince T, Matts R . Hsp90-dependent assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex. PLoS One. 2014; 9(3):e90054. PMC: 3946479. DOI: 10.1371/journal.pone.0090054. View

12.

Biebl M, Buchner J . Structure, Function, and Regulation of the Hsp90 Machinery. Cold Spring Harb Perspect Biol. 2019; 11(9). PMC: 6719599. DOI: 10.1101/cshperspect.a034017. View

13.

PIRKL F, Buchner J . Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. J Mol Biol. 2001; 308(4):795-806. DOI: 10.1006/jmbi.2001.4595. View

14.

Pearl L, Prodromou C . Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem. 2006; 75:271-94. DOI: 10.1146/annurev.biochem.75.103004.142738. View

15.

Street T, Lavery L, Agard D . Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone. Mol Cell. 2011; 42(1):96-105. PMC: 3105473. DOI: 10.1016/j.molcel.2011.01.029. View

16.

Zuehlke A, Reidy M, Lin C, LaPointe P, Alsomairy S, Lee D . An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans. Nat Commun. 2017; 8:15328. PMC: 5458067. DOI: 10.1038/ncomms15328. View

17.

Riedl S, Bilgen E, Agam G, Hirvonen V, Jussupow A, Tippl F . Evolution of the conformational dynamics of the molecular chaperone Hsp90. Nat Commun. 2024; 15(1):8627. PMC: 11452706. DOI: 10.1038/s41467-024-52995-y. View

18.

Minami Y, Kimura Y, Kawasaki H, Suzuki K, YAHARA I . The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo. Mol Cell Biol. 1994; 14(2):1459-64. PMC: 358501. DOI: 10.1128/mcb.14.2.1459-1464.1994. View

19.

Backe S, Sager R, Woodford M, Makedon A, Mollapour M . Post-translational modifications of Hsp90 and translating the chaperone code. J Biol Chem. 2020; 295(32):11099-11117. PMC: 7415980. DOI: 10.1074/jbc.REV120.011833. View

20.

Verba K, Wang R, Arakawa A, Liu Y, Shirouzu M, Yokoyama S . Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science. 2016; 352(6293):1542-7. PMC: 5373496. DOI: 10.1126/science.aaf5023. View