Mechanism of Amyloidogenesis of a Bacterial AAA plus Chaperone
Mechanism of Amyloidogenesis of a Bacterial AAA plus Chaperone
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DOI：
10.1016/j.str.2016.05.002
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发表时间：
2016-07-06
期刊：
影响因子：
5.7
通讯作者：
Houry, Walid A.
中科院分区：
文献类型：
--
作者：
Chan, Sze Wah Samuel;Yau, Jason;Houry, Walid A.
淀粉样蛋白是纤维状蛋白的上层结构，通常与人类疾病和各种生物的生理功能有关。淀粉样蛋白形成的确切机制仍有待阐明。令人惊讶的是，我们发现细菌大肠杆菌伴侣样atp酶，调节性atp酶变体a (RavA)，特别是RavA中的LARA结构域，在高温的酸性条件下形成淀粉样蛋白。RavA参与调节膜呼吸复合物的正常组装。LARA包含一个n端环区，后面是一个b-三明治状的折叠核。包括核磁共振波谱和分子动力学模拟在内的几种方法被用来确定LARA切换到淀粉样蛋白状态的机制。这些研究表明LARA的折叠核具有淀粉样变性，并受到其n端环的保护。在低pH和高温下，n端环与折叠核的相互作用被破坏，导致淀粉样蛋白的形成。
Amyloids are fibrillar protein superstructures that are commonly associated with diseases in humans and with physiological functions in various organisms. The precise mechanisms of amyloid formation remain to be elucidated. Surprisingly, we discovered that a bacterial Escherichia coli chaperone-like ATPase, regulatory ATPase variant A (RavA), and specifically the LARA domain in RavA, forms amyloids under acidic conditions at elevated temperatures. RavA is involved in modulating the proper assembly of membrane respiratory complexes. LARA contains an N-terminal loop region followed by a b-sandwich-like folded core. Several approaches, including nuclear magnetic resonance spectroscopy and molecular dynamics simulations, were used to determine the mechanism by which LARA switches to an amyloid state. These studies revealed that the folded core of LARA is amyloidogenic and is protected by its N-terminal loop. At low pH and high temperatures, the interaction of the N-terminal loop with the folded core is disrupted, leading to amyloid formation.