The Munc13 N-terminal region: a hub of protein interactions and regulatory signal processing in neurotransmitter release

Munc13 N 末端区域：神经递质释放中蛋白质相互作用和调节信号处理的中心

• 批准号: 218725433
• 负责人: Professor Dr. Manfred W. Kilimann
• 金额: --
• 依托单位: Abteilung Molekulare Neurobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218725433?language=en
• 关键词: Munc13; terminal; region; hub; protein

Neurotransmitter release is very fast and highly regulated, and several hundred proteins participate in driving and controlling it. Among these are five large multidomain proteins (Aczonin/Piccolo, Bassoon, CAST/ELKS, Munc13 and RIM), which are multiply interconnected with each other and additional proteins, and which are believed to be important for the organization of the many presynaptic proteins into an efficiently functioning “molecular machine”. Their genes were found to be mutated in several monogenic human diseases, and seem to contribute to genetically complex disorders like schizophrenia, depression, type 2 diabetes and amyotrophic lateral sclerosis (ALS). To understand the roles of these proteins in the normal and abnormal functioning of the nervous system, we need to uncover the molecular mechanisms through which they act. My laboratory has recently identified a multidomain complex in which all five proteins participate and which may constitute a hub of mechanistic interplay and regulatory signal processing. Now I aim to further elucidate the functions of this complex by a combination of approaches: a) Biochemistry (characterization of additional members of the complex; combinatorial interplay of binding partners; regulation by differential splicing, phosphorylation, Ca2+/calmodulin, diacylglycerol and Rab3 GTPases); b) Structural biology (determination of the molecular structures of domain complexes by NMR and X-ray crystallography); c) Molecular biology, electrophysiology and cell biology (selective mutagenesis and functional characterization of the roles of individual interactions and regulatory signals in neurotransmission, synaptic plasticity and synaptogenesis).

神经递质的释放是非常快速和高度调节的，数百种蛋白质参与驱动和控制它。（Aczonin/Piccolo，巴松管，CAST/ELKS，Munc 13和RIM），它们彼此和另外的蛋白质多重互连，并且被认为对于将许多突触前蛋白组织成有效功能的“分子机器”是重要的。他们的基因被发现在几种单基因人类疾病中发生突变，并且似乎有助于遗传复杂的疾病，如精神分裂症，抑郁症，2型糖尿病和肌萎缩侧索硬化症（ALS）。为了了解这些蛋白质在神经系统正常和异常功能中的作用，我们需要揭示它们发挥作用的分子机制。我的实验室最近发现了一种多结构域复合物，其中所有五种蛋白质都参与其中，并且可能构成机械相互作用和调节信号处理的中心。现在，我的目标是通过以下方法的组合进一步阐明这种复合物的功能：a）生物化学（复合物的其他成员的表征;结合配偶体的组合相互作用;通过差异剪接、磷酸化、Ca 2 +/钙调蛋白、二酰基甘油和Rab 3 GTP酶的调节）; B）结构生物学（通过NMR和X射线晶体学确定域复合物的分子结构）; c）分子生物学，电生理学和细胞生物学（选择性诱变和功能表征的作用，个别相互作用和调节信号在神经传递，突触可塑性和突触）。