Hsp110 Is a Bona Fide Chaperone Using ATP to Unfold Stable Misfolded Polypeptides and Reciprocally Collaborate with Hsp70 to Solubilize Protein Aggregates
Hsp110 Is a Bona Fide Chaperone Using ATP to Unfold Stable Misfolded Polypeptides and Reciprocally Collaborate with Hsp70 to Solubilize Protein Aggregates
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DOI：
10.1074/jbc.m113.479253
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发表时间：
2013-07-19
影响因子：
4.8
通讯作者：
Goloubinoff, Pierre
中科院分区：
文献类型：
--
作者：
Mattoo, Rayees U. H.;Sharma, Sandeep K.;Goloubinoff, Pierre
从结构和序列上看，Hsp110属于Hsp70分子伴侣的一个亚家族。像经典的Hsp70一样，Hsp110亚家族的成员可以结合错误折叠的多肽并水解三磷酸腺苷。然而，它们显然只起到从属核苷酸交换因子的作用，调节Hsp70水解三磷酸腺苷的能力，并将稳定的蛋白质聚集体转化为天然蛋白质。使用稳定错折叠和聚集的多肽作为底物进行体外伴侣优化分析，我们证明了人胞浆中的HSP110(HSPH1和HSPH2)本身是真正的伴侣，它们与Hsp40(DNAJA1和DNAJB1)合作水解ATP并解折叠，从而将稳定的错误折叠多肽转化为天然复性蛋白。此外，等摩尔HSP70(HSPA1A)和HSP110(HSPH1)形成了一个强大的分子机制，以依赖于ATP和DNAJA1的方式最佳地重新激活稳定的荧光素酶聚集体，在解聚机制中，两个平行伴侣交替激活相互结合的未折叠多肽底物的释放，导致天然蛋白折叠。
Structurally and sequence-wise, the Hsp110s belong to a subfamily of the Hsp70 chaperones. Like the classical Hsp70s, members of the Hsp110 subfamily can bind misfolding polypeptides and hydrolyze ATP. However, they apparently act as a mere subordinate nucleotide exchange factors, regulating the ability of Hsp70 to hydrolyze ATP and convert stable protein aggregates into native proteins. Using stably misfolded and aggregated polypeptides as substrates in optimized in vitro chaperone assays, we show that the human cytosolic Hsp110s (HSPH1 and HSPH2) are bona fide chaperones on their own that collaborate with Hsp40 (DNAJA1 and DNAJB1) to hydrolyze ATP and unfold and thus convert stable misfolded polypeptides into natively refolded proteins. Moreover, equimolar Hsp70 (HSPA1A) and Hsp110 ( HSPH1) formed a powerful molecular machinery that optimally reactivated stable luciferase aggregates in an ATP- and DNAJA1-dependent manner, in a disaggregation mechanism whereby the two paralogous chaperones alternatively activate the release of bound unfolded polypeptide substrates from one another, leading to native protein refolding.