| 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
Hsp104 is a ring-forming, ATP-driven molecular machine that recovers functional protein from both stress-denatured and amyloid-forming aggregates. Although Hsp104 shares a common architecture with Clp/Hsp100 protein unfoldases, different and seemingly conflicting 3D structures have been reported. Examining the structure of Hsp104 poses considerable challenges because Hsp104 readily hydrolyzes ATP, whereas ATP analogs can be slowly turned over and are often contaminated with other nucleotide species. Here, we present the single-particle electron cryo-microscopy (cryo-EM) structures of a catalytically inactive Hsp104 variant (Hsp104DWB) in the ATP-bound state determined between 7.7 A and 9.3 A resolution. Surprisingly, we observe that the Hsp104DWB hexamer adopts distinct ring conformations (closed, extended, and open) despite being in the same nucleotide state. The latter underscores the structural plasticity of Hsp104 in solution, with different conformations stabilized by nucleotide binding. Our findings suggest that, in addition to ATP hydrolysis-driven conformational changes, Hsp104 uses stochastic motions to translocate unfolded polypeptides.
Cryo-EM Structures of the Hsp104 Protein Disaggregase Captured in the ATP Conformation.,Lee S, Roh SH, Lee J, Sung N, Liu J, Tsai FTF Cell Rep. 2019 Jan 2;26(1):29-36.e3. doi: 10.1016/j.celrep.2018.12.037. PMID:30605683[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Lee S, Roh SH, Lee J, Sung N, Liu J, Tsai FTF. Cryo-EM Structures of the Hsp104 Protein Disaggregase Captured in the ATP Conformation. Cell Rep. 2019 Jan 2;26(1):29-36.e3. doi: 10.1016/j.celrep.2018.12.037. PMID:30605683 doi:http://dx.doi.org/10.1016/j.celrep.2018.12.037
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