Abstract
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.
Original language | English |
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Pages (from-to) | 680-91 |
Number of pages | 12 |
Journal | The EMBO journal |
Volume | 29 |
Issue number | 3 |
DOIs | |
Publication status | Published - 3 Feb 2010 |
Keywords
- Amino Acid Sequence
- Animals
- Calcium/metabolism
- Calmodulin/chemistry
- Humans
- Mammals
- Models, Biological
- Models, Molecular
- Molecular Conformation/drug effects
- Molecular Sequence Data
- Multiprotein Complexes/chemistry
- Nerve Tissue Proteins/chemistry
- Neuronal Plasticity/drug effects
- Sequence Homology, Amino Acid
- Structure-Activity Relationship
- Synapses/drug effects
- Time Factors