Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity
Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity
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DOI：
10.1038/nsmb1198
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发表时间：
2007-02-01
影响因子：
16.8
通讯作者：
Wickner, Sue
中科院分区：
文献类型：
--
作者：
Doyle, Shannon M.;Shorter, James;Wickner, Sue
AAA+ 超家族的两个成员 ClpB 和 Hsp104 与 Hsp70 和 Hsp40 合作拯救聚集的蛋白质。然而，引发和隐藏其蛋白质重塑活动的机制仍不清楚。我们报告说，对于 Hsp104 和 ClpB 来说，ATP 和 ATP-gamma S 的混合物意外地释放出独立于辅助伴侣的激活、解聚和展开活性。突变揭示了单个核苷酸结合域的水解受损如何引发重塑活动。然而，对于某些底物，ATP 和 ATP-gamma S 的混合物会消除重塑，而对于其他底物，ATP 结合而不水解就足够了。不同底物的重塑需要多肽“保持”（需要 ATP 结合但不需要水解）和解折叠（需要 ATP 水解）之间的不同平衡。我们认为，这种反应机制的多功能性使 ClpB 和 Hsp104 能够在应激后重新激活整个聚集的蛋白质组，并使 Hsp104 能够控制朊病毒的遗传。
Two members of the AAA+ superfamily, ClpB and Hsp104, collaborate with Hsp70 and Hsp40 to rescue aggregated proteins. However, the mechanisms that elicit and underlie their protein-remodeling activities remain unclear. We report that for both Hsp104 and ClpB, mixtures of ATP and ATP-gamma S unexpectedly unleash activation, disaggregation and unfolding activities independent of cochaperones. Mutations reveal how remodeling activities are elicited by impaired hydrolysis at individual nucleotide-binding domains. However, for some substrates, mixtures of ATP and ATP-gamma S abolish remodeling, whereas for others, ATP binding without hydrolysis is sufficient. Remodeling of different substrates necessitates a diverse balance of polypeptide 'holding' (which requires ATP binding but not hydrolysis) and unfolding (which requires ATP hydrolysis). We suggest that this versatility in reaction mechanism enables ClpB and Hsp104 to reactivate the entire aggregated proteome after stress and enables Hsp104 to control prion inheritance.