Shorter James, Lindquist Susan
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Stellar-Chance Laboratories, Philadelphia, PA 19104, USA.
EMBO J. 2008 Oct 22;27(20):2712-24. doi: 10.1038/emboj.2008.194. Epub 2008 Oct 2.
Self-templating amyloid forms of Sup35 constitute the yeast prion [PSI(+)]. How the protein-remodelling factor, Hsp104, collaborates with other chaperones to regulate [PSI(+)] inheritance remains poorly delineated. Here, we report how the Ssa and Ssb components of the Hsp70 chaperone system directly affect Sup35 prionogenesis and cooperate with Hsp104. We identify the ribosome-associated Ssb1:Zuo1:Ssz1 complex as a potent antagonist of Sup35 prionogenesis. The Hsp40 chaperones, Sis1 and Ydj1, preferentially interact with Sup35 oligomers and fibres compared with monomers, and facilitate Ssa1 and Ssb1 binding. Various Hsp70:Hsp40 pairs block prion nucleation by disassembling molten oligomers and binding mature oligomers. By binding fibres, Hsp70:Hsp40 pairs occlude prion recognition elements and inhibit seeded assembly. These inhibitory activities are partially relieved by the nucleotide exchange factor, Fes1. Low levels of Hsp104 stimulate prionogenesis and alleviate inhibition by some Hsp70:Hsp40 pairs. At high concentrations, Hsp104 eliminates Sup35 prions. This activity is reduced when Ssa1, or enhanced when Ssb1, is incorporated into nascent prions. These findings illuminate several facets of the chaperone interplay that underpins [PSI(+)] inheritance.
Sup35的自模板化淀粉样蛋白形式构成了酵母朊病毒[PSI(+)]。蛋白质重塑因子Hsp104如何与其他伴侣蛋白协作以调节[PSI(+)]的遗传，目前仍不清楚。在此，我们报告了Hsp70伴侣蛋白系统的Ssa和Ssb组分如何直接影响Sup35朊病毒的形成并与Hsp104协同作用。我们确定核糖体相关的Ssb1:Zuo1:Ssz1复合物是Sup35朊病毒形成的有效拮抗剂。与单体相比，Hsp40伴侣蛋白Sis1和Ydj1优先与Sup35寡聚体和纤维相互作用，并促进Ssa1和Ssb1的结合。各种Hsp70:Hsp40对通过拆解熔融寡聚体并结合成熟寡聚体来阻止朊病毒成核。通过结合纤维，Hsp70:Hsp40对会封闭朊病毒识别元件并抑制种子组装。核苷酸交换因子Fes1可部分缓解这些抑制活性。低水平的Hsp104刺激朊病毒形成并减轻某些Hsp70:Hsp40对的抑制作用。在高浓度时，Hsp104会消除Sup35朊病毒。当Ssa1掺入新生朊病毒时，这种活性会降低，而当Ssb1掺入时则会增强。这些发现揭示了支撑[PSI(+)]遗传的伴侣蛋白相互作用的几个方面。
