Mutations Outside the Ure2 Amyloid-Forming Region Disrupt [URE3] Prion Propagation and Alter Interactions with Protein Quality Control Factors.
Mutations Outside the Ure2 Amyloid-Forming Region Disrupt [URE3] Prion Propagation and Alter Interactions with Protein Quality Control Factors.
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Ure2 淀粉样蛋白形成区域外的突变会破坏 [URE3] 朊病毒的传播并改变与蛋白质质量控制因子的相互作用。
DOI：
10.1128/mcb.00294-20
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发表时间：
2020
影响因子：
5.3
通讯作者：
Masison,DanielC
中科院分区：
文献类型：
--
作者：
Kumar,Shailesh;Dine,ElliotA;Paddock,Ethan;Steinberg,DanielleN;Greene,LoisE;Masison,DanielC
酵母胶原蛋白[URE3]以错误折叠的Ure2蛋白的淀粉样蛋白形式繁殖。以淀粉样蛋白为基础的酵母Pron的繁殖需要蛋白质质量控制(PQC)因子，而改变PQC的丰度或活性可以治愈细胞中的Prion。由PQC因子组成的酵母反病毒系统在正常的丰度下起作用，以限制大多数新出现的病毒变异的建立。虽然这些系统已经得到了很好的描述，但它们或其他PQC因子如何与Pron蛋白相互作用仍不清楚。为了深入了解这种相互作用，我们确定了Ure2蛋白决定区域之外的突变，这些突变会破坏[URE3]的稳定性。尽管位于功能区，但17个突变体中有16个保持了Ure2的活性。四个特征突变导致[URE3]迅速丢失，但允许[URE3]在普恩选择条件下繁殖。两个对btn2、Cur1和Hsp42敏感的[URE3]，但方式不同。另外两个在体外减少了淀粉样蛋白的形成。在这些病毒中，一种是Pron复制受损，另一种明显是传播受损。因此，Pron淀粉样蛋白形成区外广泛分散的位置可能会影响Pron的特性，而改变这样的位置可能会通过改变与PQC因子的相互作用来扰乱Prion的传播。
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 arisede 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 formationin 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.