Structural and Functional Studies of Brain Angiogenesis Inhibitors (BAIs/ADGRBs)

项目摘要 细胞粘附和细胞信号之间的相互作用对于所有器官的发育都是必不可少的 例如大脑，以及神经系统等系统的功能。脑血管生成 抑制剂（BAI/ADGRB 1 -4）是一个了解甚少的粘附G蛋白偶联受体家族， 介导细胞通信。它们在突触形成和成熟中起重要作用; 与包括神经系统疾病和癌症在内的许多人类疾病有关。另一方面，在一项研究中， 神经连接素（NL）是突触后细胞粘附分子，其与突触前神经毒素（NRX）相互作用， 介导突触发生的关键功能。PI先前已经确定了以下化合物的高分辨率结构： BAI 3、NL 1和NL 1/Nrx 1复合物，并进行了功能研究，以了解它们在突触中的作用。 功能有趣的是，最近的一项研究表明，BAI 1与NL 1形成受体复合物，并介导NL 1- 依赖的棘生长和突触发育连接这两个重要的粘附受体。的 本申请中提出的研究的最终目标是了解BAI/NL的分子细节 互动我们建议获得有关BAI/NL复合物的结构和生化信息。我们将 然后利用这些结构信息研究BAI和NL相互作用在突触形成中的作用。这 研究有一个多学科的方法，其中结构和生化数据在PI的实验室进行 将由密切合作者的实验室进行的神经生物学研究进行补充。我们 预计这项研究将提供关键的洞察BAI/NL功能的机制细节，有助于 理解对大脑功能至关重要的细胞间通讯。

Project Summary The interplay between cellular adhesion and cellular signaling is essential for the development of all organs such as the brain, and for the functioning of systems such as the nervous systems. Brain Angiogenesis Inhibitors (BAIs/ADGRB1-4) are a poorly understood family of adhesion G-Protein Coupled Receptors that mediate cellular communication. They have essential roles in synapse formation and maturation; and are linked to numerous human diseases including neurological disorders and cancers. On the other hand, Neuroligins (NLs) are postsynaptic cell-adhesion molecules that interact with pre-synaptic Neurexins (NRXs) to mediate key functions in synaptogenesis. The PI has previously determined the high-resolution structures of BAI3, NL1 and the NL1/Nrx1 complex and performed functional studies to understand their roles in synapse function. Intriguingly, a recent study showed that BAI1 forms a receptor complex with NL1 and mediates NL1- dependent spine growth and synapse development linking these two important adhesion receptors. The ultimate goal of the research proposed in this application is to understand the molecular details of the BAI/NL interaction. We propose to obtain structural and biochemical information about the BAI/NL complex. We will then use the structural information to study the function of BAI and NL interaction in synapse formation. This research has a multi-disciplinary approach where the structural and biochemical data performed in the PI's lab will be complemented by the neurobiology studies performed in the laboratory of a close collaborator. We expect that this research will provide critical insights into the mechanistic details of BAI/NL function, helping to understand intercellular communication that is vital for brain functions.