Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller.
Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller.
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DOI：
10.1038/s41467-023-44479-2
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发表时间：
2024-01-02
影响因子：
16.6
通讯作者：
Lieberman, Raquel L.
中科院分区：
文献类型：
--
作者：
Saccuzzo, Emily G.;Mebrat, Mubark D.;Scelsi, Hailee F.;Kim, Minjoo;Ma, Minh Thu;Su, Xinya;Hill, Shannon E.;Rheaume, Elisa;Li, Renhao;Torres, Matthew P.;Gumbart, James C.;Van Horn, Wade D.;Lieberman, Raquel L.
使用模型蛋白系统研究折叠到错误折叠的转变，揭示了暴露淀粉样蛋白易发区域以进行随后的纤维化所需的一系列展开。在此，我们探讨了青光眼相关心肌蛋白的展开和聚集之间的关系。心肌蛋白olfactomedin结构域内的突变引起功能获得，即细胞毒性细胞内聚集，从而加速疾病进展。野生型OLF （OLFWT）的聚集与其化学展开竞争，但仅低于OLF失去三级结构的阈值。具有代表性的中度（OLFD380A）和重度（OLFI499F）疾病变异的聚集方式不同，在展开的初始阶段的发生率与OLFWT相当，并且变异采用沿OLFWT尿素展开途径可见的独特部分折叠结构。无论是由突变还是化学扰动引起的，展开都向外传播到螺旋桨表面。总之，对于这种易于形成淀粉样蛋白的大蛋白，促进淀粉样蛋白纤维化的构象改变的要求导致展开和聚集之间的直接竞争。本文探讨了青光眼相关心肌蛋白展开与淀粉样蛋白聚集的关系，发现心肌蛋白不处于平衡状态，致病性聚集与展开直接竞争。
Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLFWT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLFD380A) and severe (OLFI499F) disease variants aggregate differently, with rates comparable to OLFWT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLFWT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
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影响因子：
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作者：
Saccuzzo, Emily G.;Martin, Mackenzie D.;Hill, Kamisha R.;Minh Thu Ma;Ku, Yemo;Lieberman, Raquel L.
通讯作者：
Lieberman, Raquel L.
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通讯作者：
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