| 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.
References
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- ↑ 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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