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Modular architecture of Munc13/calmodulin complexes: dual regulation by Ca 2+ and possible function in short‐term synaptic plasticity
Author(s) -
RodríguezCastañeda Fernando,
MaestreMartínez Mitcheell,
Coudevylle Nicolas,
Dimova Kalina,
Junge Harald,
Lipstein Noa,
Lee Donghan,
Becker Stefan,
Brose Nils,
Jahn Olaf,
Carlomagno Teresa,
Griesinger Christian
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.373
Subject(s) - biology , calmodulin , synaptic plasticity , modular design , function (biology) , plasticity , dual (grammatical number) , term (time) , neuroscience , dual function , microbiology and biotechnology , computational biology , biochemistry , receptor , computer science , art , physics , thermodynamics , literature , contouring , computer graphics (images) , quantum mechanics , operating system , enzyme
Ca 2+ signalling in neurons through calmodulin (CaM) has a prominent function in regulating synaptic vesicle trafficking, transport, and fusion. Importantly, Ca 2+ –CaM binds a conserved region in the priming proteins Munc13‐1 and ubMunc13‐2 and thus regulates synaptic neurotransmitter release in neurons in response to residual Ca 2+ signals. We solved the structure of Ca 2+ 4 –CaM in complex with the CaM‐binding domain of Munc13‐1, which features a novel 1‐5‐8‐26 CaM‐binding motif with two separated mobile structural modules, each involving a CaM domain. Photoaffinity labelling data reveal the same modular architecture in the complex with the ubMunc13‐2 isoform. The N‐module can be dissociated with EGTA to form the half‐loaded Munc13/Ca 2+ 2 –CaM complex. The Ca 2+ regulation of these Munc13 isoforms can therefore be explained by the modular nature of the Munc13/Ca 2+ –CaM interactions, where the C‐module provides a high‐affinity interaction activated at nanomolar [Ca 2+ ] i , whereas the N‐module acts as a sensor at micromolar [Ca 2+ ] i . This Ca 2+ /CaM‐binding mode of Munc13 likely constitutes a key molecular correlate of the characteristic Ca 2+ ‐dependent modulation of short‐term synaptic plasticity.