Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding
Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding
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DOI：
10.1016/s1097-2765(03)00423-4
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发表时间：
2003-11-01
期刊：
影响因子：
16
通讯作者：
Frydman, J
中科院分区：
文献类型：
--
作者：
Feldman, DE;Spiess, C;Frydman, J
真核生物伴侣蛋白TRiC/CCT介导新合成蛋白质的一个重要子集的折叠，包括肿瘤抑制因子VHL。在这里，我们表明，伴侣蛋白结合指定的两个短的疏水性β链VHL，折叠后，成为埋在天然结构。这些TRiC结合决定簇被引起肿瘤的点突变破坏，这些点突变干扰伴侣蛋白缔合并导致错误折叠。引人注目的是，虽然无法在体内正确折叠，但其中一些VHL突变体在以不依赖伴侣蛋白的方式重新折叠时可以达到天然状态。TRiC/ CCT对延伸的疏水性β链的特异性可能有助于解释其在折叠聚集蛋白多肽中的作用。我们的研究结果揭示了一类致病突变，通过破坏伴侣介导的体内折叠来破坏蛋白质功能。
The eukaryotic chaperonin TRiC/CCT mediates folding of an essential subset of newly synthesized proteins, including the tumor suppressor VHL. Here we show that chaperonin binding is specified by two short hydrophobic beta strands in VHL that, upon folding, become buried within the native structure. These TRiC binding determinants are disrupted by tumor-causing point mutations that interfere with chaperonin association and lead to misfolding. Strikingly, while unable to fold correctly in vivo, some of these VHL mutants can reach the native state when refolded in a chaperonin-independent manner. The specificity of TRiC/ CCT for extended hydrophobic beta strands may help explain its role in folding aggregation-pro,ne polypeptides. Our findings reveal a class of disease-causing mutations that inactivate protein function by disrupting chaperone-mediated folding in vivo.