Reshaping of the conformational search of a protein by the chaperone trigger factor
Reshaping of the conformational search of a protein by the chaperone trigger factor
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DOI：
10.1038/nature12293
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发表时间：
2013-08-01
期刊：
影响因子：
64.8
通讯作者：
Tans, Sander J.
中科院分区：
文献类型：
--
作者：
Mashaghi, Alireza;Kramer, Guenter;Tans, Sander J.
蛋白质折叠通常被描述为一个搜索过程，其中多肽探索不同的构象以找到它们的天然结构。已知分子伴侣通过在构象搜索开始之前抑制多肽之间的聚集（1，2）以及通过在构象搜索结束之后挽救错误折叠（1，3）来提高折叠产率。虽然长期以来一直推测分子伴侣也影响构象搜索本身-通过重塑潜在的折叠景观沿着折叠轨迹（4，5）-直接的实验证据一直很少。在大肠杆菌中，一般的伴侣触发因子（6-8）（TF）可以发挥这种作用。TF已被证明与核糖体上的新生链相互作用（9，10），与从核糖体释放到胞质溶胶中的多肽相互作用（11），以及与组装成更大复合物之前完全折叠的蛋白质相互作用（12）。探讨E.利用光镊技术对麦芽糖结合蛋白（MBP）分子进行了构象搜索。在这里，我们表明，TF结合折叠结构小于一个域，然后稳定数秒，并最终转换为天然状态。此外，TF刺激在重复MBP结构域的构建体中的天然折叠。结果表明，TF通过保护部分折叠态免受产生稳定错误折叠态的远距离相互作用的影响来促进正确折叠。由于TF与大肠杆菌中大多数新合成的蛋白质相互作用，我们希望这些发现对理解蛋白质折叠途径具有普遍的重要性。
Protein folding is often described as a search process, in which polypeptides explore different conformations to find their native structure. Molecular chaperones are known to improve folding yields by suppressing aggregation between polypeptides before this conformational search starts(1,2), as well as by rescuing misfolds after it ends(1,3). Although chaperones have long been speculated to also affect the conformational search itself-by reshaping the underlying folding landscape along the folding trajectory(4,5)-direct experimental evidence has been scarce so far. In Escherichia coli, the general chaperone trigger factor(6-8) (TF) could play such a role. TF has been shown to interact with nascent chains at the ribosome(9,10), with polypeptides released from the ribosome into the cytosol(11), and with fully folded proteins before their assembly into larger complexes(12). To investigate the effect of TF from E. coli on the conformational search of polypeptides to their native state, we investigated individual maltose binding protein (MBP) molecules using optical tweezers. Here we show that TF binds folded structures smaller than one domain, which are then stable for seconds and ultimately convert to the native state. Moreover, TF stimulates native folding in constructs of repeated MBP domains. The results indicate that TF promotes correct folding by protecting partially folded states from distant interactions that produce stable misfolded states. As TF interacts with most newly synthesized proteins in E. coli, we expect these findings to be of general importance in understanding protein folding pathways.