Yan Jing, Wen Wenyu, Xu Weiguang, Long Jia-Fu, Adams Marvin E, Froehner Stanley C, Zhang Mingjie
Department of Biochemistry, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China.
EMBO J. 2005 Dec 7;24(23):3985-95. doi: 10.1038/sj.emboj.7600858. Epub 2005 Oct 27.
Pleckstrin homology (PH) domains play diverse roles in cytoskeletal dynamics and signal transduction. Split PH domains represent a unique subclass of PH domains that have been implicated in interactions with complementary partial PH domains 'hidden' in many proteins. Whether partial PH domains exist as independent structural units alone and whether two halves of a split PH domain can fold together to form an intact PH domain are not known. Here, we solved the structure of the PH(N)-PDZ-PH(C) tandem of alpha-syntrophin. The split PH domain of alpha-syntrophin adopts a canonical PH domain fold. The isolated partial PH domains of alpha-syntrophin, although completely unfolded, remain soluble in solution. Mixing of the two isolated domains induces de novo folding and yields a stable PH domain. Our results demonstrate that two complementary partial PH domains are capable of binding to each other to form an intact PH domain. We further showed that the PH(N)-PDZ-PH(C) tandem forms a functionally distinct supramodule, in which the split PH domain and the PDZ domain function synergistically in binding to inositol phospholipids.
普列克底物蛋白同源（PH）结构域在细胞骨架动力学和信号转导中发挥着多种作用。分裂型PH结构域代表了一类独特的PH结构域亚类，它们参与了与许多蛋白质中“隐藏”的互补性部分PH结构域的相互作用。部分PH结构域是否单独作为独立的结构单元存在，以及分裂型PH结构域的两个半部分是否能折叠在一起形成完整的PH结构域，目前尚不清楚。在此，我们解析了α- syntrophin的PH（N）-PDZ-PH（C）串联结构。α- syntrophin的分裂型PH结构域采用了典型的PH结构域折叠方式。α- syntrophin分离的部分PH结构域虽然完全未折叠，但在溶液中仍可溶。将两个分离的结构域混合会诱导从头折叠并产生稳定的PH结构域。我们的结果表明，两个互补的部分PH结构域能够相互结合形成完整的PH结构域。我们进一步表明，PH（N）-PDZ-PH（C）串联形成了一个功能上不同的超模块，其中分裂型PH结构域和PDZ结构域在结合肌醇磷脂时协同发挥作用。
