title: Modular architecture of Munc13/calmodulin complexes: dual regulation by Ca2+ and possible function in short-term synaptic plasticity.
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.
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Castañeda
authors.forename: Mitcheell
authors.initials: M
authors.lastname: Maestre-Martínez
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coudevylle
authors.forename: Kalina
authors.initials: K
authors.lastname: Dimova
authors.forename: Harald
authors.initials: H
authors.lastname: Junge
authors.forename: Noa
authors.initials: N
authors.lastname: Lipstein
authors.forename: Donghan
authors.initials: D
authors.lastname: Lee
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008322:Mammals; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D002147:Calmodulin; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human; D002118:Calcium