Modular architecture of Munc13/calmodulin complexes: Dual regulation by Ca 2 and possible function in short-term synaptic plasticity

Fernando Rodríguez-Castãeda, Mitcheell Maestre-Martínez, Nicolas Coudevylle, Kalina Dimova, Harald Junge, Noa Lipstein, Donghan Lee, Stefan Becker, Nils Brose, Olaf Jahn, Teresa Carlomagno, Christian Griesinger

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Ca2+ signalling in neurons through calmodulin (CaM) has a prominent function in regulating synaptic vesicle trafficking, transport, and fusion. Importantly, Ca2+-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 Ca2+signals. We solved the structure of Ca2+ 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/Ca2+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 [Ca2+] i, whereas the N-module acts as a sensor at micromolar [Ca2+] i. This Ca2+/CaM- binding mode of Munc13 likely constitutes a key molecular correlate of the characteristic Ca2+-dependent modulation of short-term synaptic plasticity.

Original languageEnglish (US)
Pages (from-to)680-691
Number of pages12
JournalEMBO Journal
Volume29
Issue number3
DOIs
StatePublished - Feb 2010
Externally publishedYes

Keywords

  • Calcium
  • Calmodulin
  • Munc13
  • Neurotransmitter release
  • Short-term plasticity

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