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

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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).