Modular architecture of Munc13/calmodulin complexes: dual regulation by Ca2+ and possible function in short-term synaptic plasticity

EMBO J. 2010 Feb 3;29(3):680-91. doi: 10.1038/emboj.2009.373. Epub 2009 Dec 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Calmodulin / chemistry
  • Calmodulin / metabolism*
  • Calmodulin / physiology
  • Humans
  • Mammals
  • Models, Biological
  • Models, Molecular
  • Molecular Conformation / drug effects
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / drug effects
  • Multiprotein Complexes / physiology*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology
  • Neuronal Plasticity* / drug effects
  • Neuronal Plasticity* / physiology
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • Synapses / drug effects
  • Synapses / metabolism
  • Time Factors


  • Calmodulin
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • UNC13B protein, human
  • Calcium