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

脑血管生成抑制剂 (BAIs/ADGRB) 的结构和功能研究

• 批准号: 9813883
• 负责人: Demet Arac-Ozkan
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813883
• 关键词: Adhesions; Affinity; Amino Acids; Angiogenesis Inhibitors; BAI1 gene; BAI2 gene; BAI3 gene; Binding; Biochemical; Biological Assay; Brain; Brain Diseases; Cell Adhesion; Cell Adhesion Molecules; Cell surface; Cells; Communication; Complement; Complex; Coupling; Crystallization; Cues; Data; Development; Disease; Excitatory Synapse; Family; G-Protein-Coupled Receptors; Genetic study; Goals; Growth; Hormones; Human; Immunity; Knowledge; Laboratories; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Molecular; Monitor; Mutate; N-terminal; Nervous system structure; Neurobiology; Neurodevelopmental Disorder; Organ; Pharmacologic Substance; Physiological; Proteins; Research; Resolution; Role; Schizophrenia; Signal Transduction; Structure; Structure-Activity Relationship; Synapses; System; Transmembrane Domain; Vertebral column; Work; X-Ray Crystallography; adhesion receptor; anticancer research; deafness; design; experimental study; extracellular; follow-up; human disease; in vivo; insight; intercellular communication; interdisciplinary approach; malignant neurologic neoplasms; member; mutant; nervous system disorder; neuroligin 1; neuroligin 3; novel; novel strategies; novel therapeutics; postsynaptic; protein function; receptor; success; synaptic function; synaptogenesis; tool

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.

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展至关重要 例如大脑，以及神经系统等系统的功能。脑血管生成 抑制剂（BAIS/ADGRB1-4）是一个知名度不足的粘附家族G蛋白偶联受体， 介导细胞通信。它们在突触形成和成熟中具有重要作用。是 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， 神经素（NLS）是与突触前神经毒素（NRX）相互作用的突触后细胞粘附分子 介导突触发生中的关键功能。 PI先前已经确定了高分辨率结构 BAI3，NL1和NL1/NRX1复合物并进行了功能研究，以了解其在突触中的作用 功能。有趣的是，最近的一项研究表明，BAI1与NL1形成受体复合物，并介导NL1-- 依赖性的脊柱生长和突触发展将这两个重要的粘附受体联系起来。这 本应用中提出的研究的最终目标是了解BAI/NL的分子细节 相互作用。我们建议获得有关BAI/NL复合物的结构和生化信息。我们将 然后使用结构信息研究BAI和NL相互作用在突触形成中的功能。这 研究具有多学科的方法，其中在PI实验室中执行的结构和生化数据 在密切合作者的实验室中进行的神经生物学研究将补充。我们 预计这项研究将为BAI/NL功能的机械细节提供重要的见解，有助于 了解对大脑功能至关重要的细胞间通信。