Karanicolas John, Brooks Charles L
Department of Molecular Biology (TPC6), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3954-9. doi: 10.1073/pnas.0731771100. Epub 2003 Mar 24.
The mechanism of formation of beta-sheets is of great importance because of the significant role of such structures in the initiation and propagation of amyloid diseases. In this study we examine the folding of a series of three-stranded antiparallel beta-sheets known as WW domains. Whereas other WW domains have been shown to fold with single-exponential kinetics, the WW domain from murine formin-binding protein 28 has recently been shown to fold with biphasic kinetics. By using a combination of kinetics and thermodynamics to characterize a simple model for this protein, the origins of the biphasic kinetics is found to lie in the fact that most of the protein is able to fold without requiring one of the beta-hairpins to be correctly registered. The correct register of this hairpin is enforced by a surface-exposed hydrophobic contact, which is not present in other WW domains. This finding suggests the use of judiciously chosen surface-exposed hydrophobic pairs as a protein design strategy for enforcing the desired strand registry.
β-折叠的形成机制非常重要，因为这种结构在淀粉样疾病的起始和传播中起着重要作用。在本研究中，我们研究了一系列被称为WW结构域的三链反平行β-折叠的折叠情况。虽然其他WW结构域已被证明以单指数动力学折叠，但最近发现来自小鼠formin结合蛋白28的WW结构域以双相动力学折叠。通过结合动力学和热力学来表征该蛋白质的一个简单模型，发现双相动力学的起源在于大多数蛋白质能够在不需要其中一个β-发夹正确对齐的情况下折叠。这个发夹的正确对齐是由一个表面暴露的疏水接触强制实现的，而其他WW结构域中不存在这种接触。这一发现表明，使用精心选择的表面暴露疏水对作为一种蛋白质设计策略，以强制实现所需的链对齐。
