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Mutations outside Ure2 amyloid-forming region disrupt [URE3] prion propagation, alter interactions with protein quality control factors.
Molecular and Cellular Biology ( IF 3.2 ) Pub Date : 2020-10-13 , DOI: 10.1128/mcb.00294-20
Shailesh Kumar 1 , Elliot A Dine 1 , Ethan Paddock 1 , Danielle N Steinberg 2 , Lois E Greene 2 , Daniel C Masison 3
Affiliation  

The yeast prion [URE3] propagates as a misfolded amyloid form of the Ure2 protein. Propagation of amyloid-based yeast prions requires protein quality control (PQC) factors, and altering PQC abundance or activity can cure cells of prions. Yeast antiprion systems composed of PQC factors act at normal abundance to restrict establishment of the majority of prion variants that arise de novo. While these systems are well described, how they or other PQC factors interact with prion proteins remains unclear. To gain insight into such interactions, we identified mutations outside the Ure2 prion-determining region that destabilize [URE3]. Despite residing in the functional domain, 16 of 17 mutants retained Ure2 activity. Four characterized mutations caused rapid loss of [URE3] yet allowed [URE3] to propagate under prion-selecting conditions. Two sensitized [URE3] to Btn2, Cur1, and Hsp42, but in different ways. Two others reduced amyloid formation in vitro. Of these, one impaired prion replication and the other apparently impaired transmission. Thus, widely dispersed sites outside a prion’s amyloid-forming region can contribute to prion character, and altering such sites can disrupt prion propagation by altering interactions with PQC factors.

中文翻译:

Ure2淀粉样蛋白形成区域以外的突变破坏[URE3] ion病毒的传播,改变与蛋白质质量控​​制因子的相互作用。

酵母病毒[URE3]以Ure2蛋白的错误折叠的淀粉样形式传播。基于淀粉样蛋白的酵母病毒的繁殖需要蛋白质质量控​​制(PQC)因素,而改变PQC的丰度或活性可以治愈cells病毒的细胞。由PQC因子组成的酵母抗pr病毒系统以正常丰度发挥作用,限制了从头产生的大多数of病毒变体的建立。尽管已经很好地描述了这些系统,但还不清楚它们或其他PQC因子如何与病毒蛋白相互作用。为了深入了解此类相互作用,我们鉴定了Ure2 ion病毒决定区域之外的不稳定基因[URE3]。尽管位于功能区中,但17个突变体中的16个仍保留了Ure2活性。四个特征性突变导致[URE3]的快速丢失,但仍允许[URE3]在病毒选择条件下传播。两个人使[URE3]对Btn2,Cur1和Hsp42敏感,但方式不同。另外两个在体外减少了淀粉样蛋白的形成。其中,一种损害one病毒复制,另一种显然损害传播。因此,在dispersed病毒的淀粉样蛋白形成区域之外广泛分散的位点可有助于病毒的特性,改变这些位点可通过改变与PQC因子的相互作用而破坏病毒的传播。
更新日期:2020-10-13
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