Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Structure. 2010 Aug 11;18(8):1044-53. doi: 10.1016/j.str.2010.06.005.
Neurexins are multidomain synaptic cell-adhesion proteins that associate with multiple partnering proteins. Genetic evidence indicates that neurexins may contribute to autism, schizophrenia, and nicotine dependence. Using analytical ultracentrifugation, single-particle electron microscopy, and solution X-ray scattering, we obtained a three-dimensional structural model of the entire extracellular domain of neurexin-1alpha. This protein adopts a dimensionally asymmetric conformation that is monomeric in solution, with a maximum dimension of approximately 170 A. The extracellular domain of alpha-neurexin maintains a characteristic "Y" shape, whereby LNS domains 1-4 form an extended base of the "Y" and LNS5-6 the shorter arms. Moreover, two major regions of flexibility are present: one between EGF1 and LNS2, corresponding to splice site 1, another between LNS5 and 6. We thus provide the first structural insights into the architecture of the extracellular region of neurexin-1alpha, show how the protein may fit in the synaptic cleft, and how partnering proteins could bind simultaneously.
神经连接蛋白是一种具有多个结构域的突触细胞黏附蛋白，可与多种相互作用的蛋白结合。遗传证据表明，神经连接蛋白可能与自闭症、精神分裂症和尼古丁依赖有关。我们利用分析超速离心、单颗粒电子显微镜和溶液 X 射线散射技术，获得了神经连接蛋白 1α 整个细胞外结构域的三维结构模型。该蛋白呈非对称构象，在溶液中为单体，最大尺寸约为 170Å。α-神经连接蛋白的细胞外结构域保持特征性的“Y”形，LNS 结构域 1-4 形成“Y”的延伸基底，LNS5-6 则形成较短的臂。此外，存在两个主要的柔性区域：一个位于 EGF1 和 LNS2 之间，对应于剪接位点 1，另一个位于 LNS5 和 6 之间。因此，我们首次提供了神经连接蛋白 1α 细胞外区域结构的结构见解，展示了该蛋白如何适合在突触间隙中，以及如何同时结合相互作用的蛋白。
