Feldman Douglas E, Spiess Christoph, Howard Daniel E, Frydman Judith
Department of Biological Sciences and BioX Program, Stanford University, E200A James Clark Center, 318 Campus Drive, Stanford, CA 94305, USA.
Mol Cell. 2003 Nov;12(5):1213-24. doi: 10.1016/s1097-2765(03)00423-4.
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-prone polypeptides. Our findings reveal a class of disease-causing mutations that inactivate protein function by disrupting chaperone-mediated folding in vivo.
真核伴侣蛋白TRiC/CCT介导新合成蛋白质中一个重要子集的折叠，其中包括肿瘤抑制因子VHL。我们在此表明，伴侣蛋白结合由VHL中的两条短疏水β链决定，这两条链在折叠时会埋入天然结构中。这些TRiC结合决定簇会被导致肿瘤的点突变破坏，这些突变会干扰伴侣蛋白的结合并导致错误折叠。引人注目的是，虽然这些VHL突变体中的一些在体内无法正确折叠，但当以不依赖伴侣蛋白的方式重新折叠时，它们可以达到天然状态。TRiC/CCT对延伸的疏水β链的特异性可能有助于解释其在折叠易聚集多肽中的作用。我们的研究结果揭示了一类致病突变，这类突变通过破坏体内伴侣蛋白介导的折叠来使蛋白质功能失活。
