蛋白质折叠问题是分子生物学中心法则尚未解决的一个重大生物学问题。近日，德国科学家实验发现，蛋白质折叠过程中分子伴侣亚基能够增强异构酶的活性，两者功能的联合产生了高效的蛋白质折叠辅助作用。相关研究成果发表在近期的《美国国家科学院院刊》上。
氨基酸链必须折叠成特定的空间结构，蛋白质才具有生物学功能。当一种蛋白质没有正确地折叠时，会导致很多种疾病，例如镰刀型细胞贫血症、疯牛病和老年痴呆症等。因此，蛋白质折叠问题也是生命科学领域的前沿课题之一，与人类健康密切相关。
近年来的研究表明，特定的异构酶有促进蛋白质折叠的功能。其原因在于连接氨基酸的肽键有顺式和反式两种异构体，顺式肽键允许形成细长的肽链，反式肽键则导致肽链的扭结，特定的异构酶可促进上述顺反两种异构体之间的转换。如果缺少所需的异构酶，这个转换的过程就会非常缓慢。另一类有折叠辅助作用的是分子伴侣，它可识别肽链的非天然构象并与之结合，防止错误折叠或产生不溶物，完成功能后与之分离，不构成这些蛋白质执行功能时的组分。不过，上述两种辅助折叠功能协同合作的机理一直不清楚。
德国拜罗伊特大学和马克斯—普朗克蛋白质折叠酶学研究站科学家的最新研究表明，在辅助折叠蛋白链时，有分子伴侣亚基的帮助，脯氨酸异构酶对不同的氨基酸都能起到同样好的效果。科学家描述了一种机制来说明这些酶是如何使用它们的亚基来作为最佳折叠酶工作的。首先，分子伴侣的亚基俘获那些尚未折叠的肽链，然后把它们交给异构酶的亚基。这个很快就完成的传递过程简化了异构酶亚基的工作。异构酶的工作速度很可能取决于这两个功能中心的传递情况。
上述结论是科学家通过比较两种不同的酶得出的，一种酶仅拥有脯氨酸异构酶亚基，另一种除了催化亚基外还拥有伴侣分子亚基。在没有分子伴侣亚基的情况下，异构酶活性高度依赖于脯氨酸序列周围相对应的短肽和待折叠的蛋白链。而有了分子伴侣亚基的存在，蛋白质折叠的活动大幅度增加，且独立于氨基酸的化学性质。未折叠的蛋白链与分子伴侣的良好结合可确保其很好的折叠，并且可用与序列无关的折叠酶来加速。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS November 17, 2009, doi: 10.1073/pnas.0909544106
Chaperone domains convert prolyl isomerases into generic catalysts of protein folding
Roman P. Jakoba, Gabriel Zoldáka, Tobias Aumüllerb and Franz X. Schmida,1
aLaboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biowissenschaften, Universit?t Bayreuth, D-95440 Bayreuth, Germany; and
bMax Planck Research Unit for Enzymology of Protein Folding, D-06120 Halle/Saale, Germany
The cis/trans isomerization of peptide bonds before proline (prolyl bonds) is a rate-limiting step in many protein folding reactions, and it is used to switch between alternate functional states of folded proteins. Several prolyl isomerases of the FK506-binding protein family, such as trigger factor, SlyD, and FkpA, contain chaperone domains and are assumed to assist protein folding in vivo. The prolyl isomerase activity of FK506-binding proteins strongly depends on the nature of residue Xaa of the Xaa-Pro bond. We confirmed this in assays with a library of tetrapeptides in which position Xaa was occupied by all 20 aa. A high sequence specificity seems inconsistent with a generic function of prolyl isomerases in protein folding. Accordingly, we constructed a library of protein variants with all 20 aa at position Xaa before a rate-limiting cis proline and used it to investigate the performance of trigger factor and SlyD as catalysts of proline-limited folding. The efficiencies of both prolyl isomerases were higher than in the tetrapeptide assays, and, intriguingly, this high activity was almost independent of the nature of the residue before the proline. Apparently, the almost indiscriminate binding of the chaperone domain to the refolding protein chain overrides the inherently high sequence specificity of the prolyl isomerase site. The catalytic performance of these folding enzymes is thus determined by generic substrate recognition at the chaperone domain and efficient transfer to the active site in the prolyl isomerase domain.
