Ranson N A, Dunster N J, Burston S G, Clarke A R
Department of Biochemistry, University of Bristol School of Medical Sciences, UK.
J Mol Biol. 1995 Jul 28;250(5):581-6. doi: 10.1006/jmbi.1995.0399.
Chaperonins use energy derived from ATP hydrolysis to enhance the efficiency of protein folding by a mechanism which remains a matter of debate. Here, we show that the kinetics of spontaneous and assisted folding of mitochondrial malate dehydrogenase are quantitatively described by a simple physical model. The protein folds from non-native chains by the slow formation of native-like monomers, which then dimerize to form the active enzyme. Misfolding proceeds by two phases of aggregation: the first is slowly reversible, the second is irreversible. Chaperonins accelerate the dissociation of the first-formed, unstable aggregates through a repeated binding-and-release cycle coupled to ATP hydrolysis. By this catalytic action, they supply the productive folding pathway with monomers, and block the irreversible phase of aggregation, thereby maintaining optimal folding yields even when present in sub-stoichiometric quantities. The hydrolytically active chaperonin is required until the substrate protein has completed the slow transition to its native-like, monomeric state. Both the observed rate of folding and the yield are increased by this mechanism without changing real rates in the productive pathway.
伴侣蛋白利用ATP水解产生的能量，通过一种仍存在争议的机制来提高蛋白质折叠的效率。在此，我们表明线粒体苹果酸脱氢酶的自发折叠和辅助折叠动力学可以用一个简单的物理模型进行定量描述。该蛋白质从非天然链通过缓慢形成类似天然的单体进行折叠，然后二聚化形成活性酶。错误折叠通过两个聚集阶段进行：第一个阶段是缓慢可逆的，第二个阶段是不可逆的。伴侣蛋白通过与ATP水解偶联的重复结合和释放循环，加速首先形成的不稳定聚集体的解离。通过这种催化作用，它们为高效折叠途径提供单体，并阻断聚集的不可逆阶段，从而即使在亚化学计量存在时也能保持最佳的折叠产率。直到底物蛋白完成向其类似天然的单体状态的缓慢转变，都需要具有水解活性的伴侣蛋白。通过这种机制，观察到的折叠速率和产率都增加了，而不会改变高效折叠途径中的实际速率。
