Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients.
Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients.
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DOI：
10.1016/j.cell.2012.09.038
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发表时间：
2012-11-09
期刊：
影响因子：
64.5
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
DeSantis ME;Leung EH;Sweeny EA;Jackrel ME;Cushman-Nick M;Neuhaus-Follini A;Vashist S;Sochor MA;Knight MN;Shorter J
目前尚不清楚Hsp 104（一种来自酵母的六聚AAA+ ATP酶）如何解聚多种结构，包括与帕金森病相关的应激诱导的聚集体、朊病毒和α-突触核蛋白构象异构体。在这里，我们建立了热休克蛋白104六聚体适应不同的机制，亚基间的合作，解聚应力诱导的聚集体与淀粉样蛋白。为了解决无序聚集体，Hsp 104亚基通过概率底物结合和ATP水解非合作地协作。为了分解淀粉样蛋白，几个亚基协同作用于底物并水解ATP。重要的是，亚基间通讯受损的Hsp 104变体溶解无序聚集体，但不溶解淀粉样蛋白。出乎意料的是，原核ClpB亚基的合作不同于热休克蛋白104和夫妇的概率底物结合合作ATP水解，这增强了无序的聚集体溶解，但敏感ClpB抑制和减少淀粉样蛋白解聚。最后，我们建立了Hsp 104六聚体部署更多的亚基，以解聚具有更稳定的“交叉β”核心的Sup 35朊病毒株。因此，操作可塑性使HSP 104能够稳健地溶解淀粉样蛋白和非淀粉样蛋白客户端，这施加了不同的机械要求。
It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate non-co-operatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits co-operatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable ‘cross-β’ cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and non-amyloid clients, which impose distinct mechanical demands.
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