Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg, Germany.
Nat Struct Mol Biol. 2018 Jan;25(1):83-89. doi: 10.1038/s41594-017-0008-2. Epub 2018 Jan 1.
Protein quality control depends on the tight regulation of interactions between molecular chaperones and polypeptide substrates. Substrate release from the chaperone Hsp70 is triggered by nucleotide-exchange factors (NEFs) that control folding and degradation fates via poorly understood mechanisms. We found that the armadillo-type NEFs budding yeast Fes1 and its human homolog HspBP1 employ flexible N-terminal release domains (RDs) with substrate-mimicking properties to ensure the efficient release of persistent substrates from Hsp70. The RD contacts the substrate-binding domain of the chaperone, competes with peptide substrate for binding and is essential for proper function in yeast and mammalian cells. Thus, the armadillo domain engages Hsp70 to trigger nucleotide exchange, whereas the RD safeguards the release of substrates. Our findings provide fundamental mechanistic insight into the functional specialization of Hsp70 NEFs and have implications for the understanding of proteostasis-related disorders, including Marinesco-Sjögren syndrome.
蛋白质质量控制依赖于分子伴侣和多肽底物之间相互作用的严格调节。分子伴侣 Hsp70 上底物的释放是由核苷酸交换因子（NEFs）触发的，这些因子通过尚未完全理解的机制控制折叠和降解命运。我们发现，酵母 Fes1 和其人类同源物 HspBP1 等类骨质 NEFs 采用具有底物模拟特性的灵活 N 端释放结构域（RD），以确保从 Hsp70 上有效释放持续存在的底物。RD 与伴侣的底物结合域结合，与肽底物竞争结合，对于酵母和哺乳动物细胞中的正确功能是必需的。因此，类骨质结构域与 Hsp70 结合以触发核苷酸交换，而 RD 则确保底物的释放。我们的发现为 Hsp70 NEFs 的功能专业化提供了基本的机制见解，并对包括 Marinesco-Sjögren 综合征在内的与蛋白质稳定性相关的疾病的理解具有重要意义。
