Lang K, Schmid F X, Fischer G
Nature. 1987;329(6136):268-70. doi: 10.1038/329268a0.
Rates of protein folding reactions vary considerably. Some denatured proteins regain the native conformation within milliseconds or seconds, whereas others refold very slowly in the time range of minutes or hours. Varying folding rates are observed not only for different proteins, but can also be detected for single polypeptide species. This originates from the co-existence of fast- and slow-folding forms of the unfolded protein, which regain the native state with different rates. The proline hypothesis provides a plausible explanation for this heterogeneity. It assumes that the slow-folding molecules possess non-native isomers of peptide bonds between proline and another residue, and that crucial steps in the refolding of the slow-folding molecules are limited in rate by the slow reisomerization of such incorrect proline peptide bonds. Recently the enzyme peptidyl-prolyl cis-trans isomerase (PPIase) was discovered and purified from pig kidney. It catalyses efficiently the cis in equilibrium trans isomerization of proline imidic peptide bonds in oligopeptides. Here we show that it also catalyses slow steps in the refolding of a number of proteins of which fast- and slow-folding species have been observed and where it was suggested that proline isomerization was involved in slow refolding. The efficiency of catalysis depends on the accessibility for the isomerase of the particular proline peptide bonds in the refolding protein chain.
蛋白质折叠反应的速率差异很大。一些变性蛋白质能在几毫秒或几秒内重新获得天然构象，而另一些则在几分钟或几小时的时间范围内非常缓慢地重新折叠。不仅不同的蛋白质存在不同的折叠速率，对于单一多肽种类也能检测到这种差异。这源于未折叠蛋白质的快速折叠形式和缓慢折叠形式共存，它们以不同速率重新获得天然状态。脯氨酸假说是对这种异质性的一种合理解释。该假说认为，缓慢折叠的分子在脯氨酸与另一个残基之间存在肽键的非天然异构体，并且缓慢折叠分子重新折叠的关键步骤受此类不正确脯氨酸肽键缓慢的重新异构化限制。最近，肽基脯氨酰顺反异构酶（PPIase）从猪肾中被发现并纯化。它能高效催化寡肽中脯氨酸亚胺肽键的顺反异构化平衡。在此我们表明，它还能催化一些蛋白质重新折叠过程中的缓慢步骤，这些蛋白质存在快速折叠和缓慢折叠的种类，并且有人认为脯氨酸异构化参与了缓慢折叠过程。催化效率取决于异构酶对重新折叠蛋白质链中特定脯氨酸肽键的可及性。
