| Structural highlights
Function
HS104_YEAST Required, in concert with Hsp40 (YDJ1) and Hsp70 (SSA1) and small Hsps (HSP26), for the dissociation, resolubilization and refolding of aggregates of damaged proteins after heat or other environmental stresses. Extracts proteins from aggregates by unfolding and threading them in an ATP-dependent process through the axial channel of the protein hexamer, after which they can be refolded by components of the Hsp70/Hsp40 chaperone system. Substrate binding is ATP-dependent, and release of bound polypeptide is triggered by ATP hydrolysis. Also responsible for the maintenance of prions by dissociating prion fibrils into smaller oligomers, thereby producing transmissible seeds that can infect daughter cells during mitosis and meiosis. Loss of HSP104 can cure yeast cells of the prions [PSI+], [URE3] and [PIN+]. Excess HSP104 can also specifically cure cells of [PSI+].[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
Publication Abstract from PubMed
Heat shock protein 104 (HSP104) is a conserved AAA+ protein disaggregase, can disassemble the toxic aggregates formed by different amyloid proteins, and is protective in various animal models associated with amyloid-related diseases. Extensive studies have attempted to elucidate how HSP104 disassembles the aggregated form of clients. Here, we found that HSP104 exhibits a potent holdase activity that does not require energy, prevents the soluble form of amyloid clients from aggregating, and differs from HSP104's disaggregase activity. Using cryo-EM, NMR and additional biophysical approaches, we found that HSP104 utilizes its small subdomain of nucleotide-binding domain 2 (ssNBD2) to capture the soluble amyloid client (K19 of Tau) independent of its ATP hydrolysis activity. Our results indicate that HSP104 utilizes two fundamental distinct mechanisms to chaperone different forms of amyloid client and highlight the important yet previously unappreciated function of ssNBD2 in chaperoning amyloid client and thereby preventing pathological aggregation.
Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity.,Zhang X, Zhang S, Zhang L, Lu J, Zhao C, Luo F, Li D, Li X, Liu C J Biol Chem. 2019 Feb 4. pii: RA118.005980. doi: 10.1074/jbc.RA118.005980. PMID:30718279[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Cashikar AG, Duennwald M, Lindquist SL. A chaperone pathway in protein disaggregation. Hsp26 alters the nature of protein aggregates to facilitate reactivation by Hsp104. J Biol Chem. 2005 Jun 24;280(25):23869-75. Epub 2005 Apr 20. PMID:15845535 doi:http://dx.doi.org/M502854200
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- ↑ Doyle SM, Shorter J, Zolkiewski M, Hoskins JR, Lindquist S, Wickner S. Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nat Struct Mol Biol. 2007 Feb;14(2):114-22. Epub 2007 Jan 28. PMID:17259993 doi:http://dx.doi.org/nsmb1198
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- ↑ Chernoff YO, Lindquist SL, Ono B, Inge-Vechtomov SG, Liebman SW. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science. 1995 May 12;268(5212):880-4. PMID:7754373
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- ↑ Glover JR, Lindquist S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell. 1998 Jul 10;94(1):73-82. PMID:9674429
- ↑ Zhang X, Zhang S, Zhang L, Lu J, Zhao C, Luo F, Li D, Li X, Liu C. Heat shock protein 104 (HSP104) chaperones soluble Tau via a mechanism distinct from its disaggregase activity. J Biol Chem. 2019 Feb 4. pii: RA118.005980. doi: 10.1074/jbc.RA118.005980. PMID:30718279 doi:http://dx.doi.org/10.1074/jbc.RA118.005980
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