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

项目摘要 细胞黏附和细胞信号之间的相互作用对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 抑制物(Bais/ADGRB1-4)是一个知之甚少的黏附G蛋白偶联受体家族 调节蜂窝通信。它们在突触的形成和成熟过程中起着至关重要的作用； 与许多人类疾病有关，包括神经疾病和癌症。另一方面， 神经连接蛋白(NLS)是突触后细胞黏附分子，与突触前神经尿苷(NRXs)相互作用 调节突触发生中的关键功能。PI之前已经确定了高分辨率结构 BAI3、NL1和NL1/Nrx1复合体，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，BAI1与Nl1形成受体复合体，并介导Nl1- 依赖脊椎生长和突触发育连接这两个重要的黏附受体。这个 本申请中提出的研究的最终目的是了解BAI/NL的分子细节 互动。我们建议获得关于BAI/NL复合体的结构和生化信息。我们会 然后利用结构信息研究BAI和NL相互作用在突触形成中的作用。这 研究采用了多学科方法，在PI的实验室中执行的结构和生化数据 将得到在密切合作者的实验室进行的神经生物学研究的补充。我们 预计这项研究将为BAI/NL功能的机制细节提供关键的见解，有助于 了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.