Structural mechanisms of chaperone mediated protein disaggregation.
Structural mechanisms of chaperone mediated protein disaggregation.
复制标题
伴侣介导的蛋白质分解的结构机制。
DOI：
10.3389/fmolb.2014.00012
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发表时间：
2014
影响因子：
5
通讯作者：
Sousa R
中科院分区：
文献类型：
--
作者：
Sousa R
ClpB/Hsp 104和Hsp 70类分子伴侣使用ATP水解来解离蛋白质聚集体和复合物，并使蛋白质穿过膜。ClpB/Hsp 104是形成环形六聚体的AAA+蛋白质家族的成员。环中排列在孔中的环与底物蛋白结合为延伸的多肽。这些环中的结构域间旋转和构象变化与ATP水解偶联，展开并拉动蛋白质穿过孔。这提供了一种逐渐破坏底物中局部二级和三级结构的机制，使这些分子伴侣解离稳定的聚集体，如富含β-折叠的朊病毒或卷曲螺旋SNARE复合物。虽然ClpB/Hsp 104机制似乎体现了真正的动力冲程，其中一种蛋白质中的ATP动力构象变化直接与另一种蛋白质中的运动或结构变化相耦合，但Hsp 70产生力的机制是独特的，并且不太清楚。主动功率冲程和纯粹被动的机制，其中热休克蛋白70捕获自发波动的基板已被提出，而第三个提出的机制熵拉，可能能够产生的力量大于看到ATP驱动的分子马达没有构象耦合所需的功率冲程。这些分子伴侣的解聚酶活性是耐热性所必需的，但不受限制的蛋白质复合物/聚集体解离是潜在有害的。解聚分子伴侣是强烈自阻遏的，并且由共分子伴侣调节，共分子伴侣将解聚分子伴侣募集到蛋白质底物并通过涉及底物从一个分子伴侣顺序转移到另一个分子伴侣和/或底物与多个分子伴侣同时相互作用的机制激活解聚剂。通过有效地使底物经受多个分子伴侣的多个水平的选择，这可以确保这些有效的解聚剂仅在适当的情况下被激活。
The ClpB/Hsp104 and Hsp70 classes of molecular chaperones use ATP hydrolysis to dissociate protein aggregates and complexes, and to move proteins through membranes. ClpB/Hsp104 are members of the AAA+ family of proteins which form ring-shaped hexamers. Loops lining the pore in the ring engage substrate proteins as extended polypeptides. Interdomain rotations and conformational changes in these loops coupled to ATP hydrolysis unfold and pull proteins through the pore. This provides a mechanism that progressively disrupts local secondary and tertiary structure in substrates, allowing these chaperones to dissociate stable aggregates such as β-sheet rich prions or coiled coil SNARE complexes. While the ClpB/Hsp104 mechanism appears to embody a true power-stroke in which an ATP powered conformational change in one protein is directly coupled to movement or structural change in another, the mechanism of force generation by Hsp70s is distinct and less well understood. Both active power-stroke and purely passive mechanisms in which Hsp70 captures spontaneous fluctuations in a substrate have been proposed, while a third proposed mechanism—entropic pulling—may be able to generate forces larger than seen in ATP-driven molecular motors without the conformational coupling required for a power-stroke. The disaggregase activity of these chaperones is required for thermotolerance, but unrestrained protein complex/aggregate dissociation is potentially detrimental. Disaggregating chaperones are strongly auto-repressed, and are regulated by co-chaperones which recruit them to protein substrates and activate the disaggregases via mechanisms involving either sequential transfer of substrate from one chaperone to another and/or simultaneous interaction of substrate with multiple chaperones. By effectively subjecting substrates to multiple levels of selection by multiple chaperones, this may insure that these potent disaggregases are only activated in the appropriate context.