A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity?

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Abstract
α‐RIMs and Munc13s are active zone proteins that control priming of synaptic vesicles to a readily releasable state, and interact with each other via their N‐terminal sequences. The α‐RIM N‐terminal sequence also binds to Rab3s (small synaptic vesicle GTPases), an interaction that regulates presynaptic plasticity. We now demonstrate that α‐RIMs contain adjacent but separate Munc13‐ and Rab3‐binding sites, allowing formation of a tripartite Rab3/RIM/Munc13 complex. Munc13 binding is mediated by the α‐RIM zinc‐finger domain. Elucidation of the three‐dimensional structure of this domain by NMR spectroscopy facilitated the design of a mutation that abolishes α‐RIM/Munc13 binding. Selective disruption of this interaction in the calyx of Held synapse decreased the size of the readily releasable vesicle pool. Our data suggest that the ternary Rab3/RIM/Munc13 interaction approximates synaptic vesicles to the priming machinery, providing a substrate for presynaptic plasticity. The modular architecture of α‐RIMs, with nested binding sites for Rab3 and other targets, may be a general feature of Rab effectors that share homology with the α‐RIM N‐terminal sequence.