Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation.
Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation.
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DOI：
10.1038/nsmb.3277
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发表时间：
2016-09
影响因子：
16.8
通讯作者：
Southworth DR
中科院分区：
文献类型：
--
作者：
Yokom AL;Gates SN;Jackrel ME;Mack KL;Su M;Shorter J;Southworth DR
ClpB和Hsp104是在细胞应激期间促进存活的保守的AAA+蛋白解聚剂。热休克蛋白104作用于淀粉样蛋白，支持朊病毒在酵母中的繁殖，并能溶解与神经退行性疾病有关的有毒寡聚体。然而，一个确定的结构机制仍然难以捉摸。我们已经确定了热休克蛋白104在ATP状态下的冷冻电镜结构，揭示了一个近螺旋的六聚体结构，协调12个AAA+结构域的机械功率解聚。一个前所未有的异聚AAA+的相互作用定义了一个明显的催化安排，对齐的结构域在一个两转螺旋的不对称缝。N末端结构域相互作用，形成底物接合和Hsp70相互作用的宽通道入口。中间结构域的螺旋桥接相邻的原聚体跨越核苷酸口袋，解释水解和解聚的作用。值得注意的是，底物结合孔环以连续螺旋排列通道，其似乎优化了底物跨AAA+结构域的转移，建立了多肽易位的定向路径。
ClpB and Hsp104 are conserved AAA+ protein disaggregases that promote survival during cellular stress. Hsp104 acts on amyloids, supporting prion propagation in yeast, and can solubilize toxic oligomers connected to neurodegenerative diseases. A definitive structural mechanism, however, has remained elusive. We have determined the cryo-EM structure of Hsp104 in the ATP state, revealing a near-helical hexamer architecture that coordinates the mechanical power of the twelve AAA+ domains for disaggregation. An unprecedented heteromeric AAA+ interaction defines an asymmetric seam in an apparent catalytic arrangement that aligns the domains in a two-turn spiral. N-terminal domains interact to form a broad channel entrance for substrate engagement and Hsp70 interaction. Middle-domain helices bridge adjacent protomers across the nucleotide pocket, explaining roles in hydrolysis and disaggregation. Remarkably, substrate-binding pore loops line the channel in a continuous spiral that appears optimized for substrate transfer across the AAA+ domains, establishing a directional path for polypeptide translocation.
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