RGD Reference Report - Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. - Rat Genome Database

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Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.

Authors: Lu, J  Machius, M  Dulubova, I  Dai, H  Sudhof, TC  Tomchick, DR  Rizo, J 
Citation: Lu J, etal., PLoS Biol. 2006 Jul;4(7):e192.
RGD ID: 2311136
Pubmed: PMID:16732694   (View Abstract at PubMed)
PMCID: PMC1472246   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pbio.0040192   (Journal Full-text)

C(2) domains are well characterized as Ca(2+)/phospholipid-binding modules, but little is known about how they mediate protein-protein interactions. In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13-1 C(2)A domain homodimerizes, and that homodimerization competes with Munc13-1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively. The C(2)A domain adopts a beta-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded beta-barrel. In contrast, heterodimerization involves the bottom tip of the C(2)A-domain beta-sandwich and a C-terminal alpha-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13-1 homodimer-Munc13-1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C(2) domains as protein-protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes.



Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rims2Ratprotein-containing complex  IDA  RGD 
Unc13aRatprotein-containing complex  IDA  RGD 

Molecular Function
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Unc13aRatidentical protein binding enablesIPIUniProtKB:Q62768PMID:16732694IntAct 
Unc13aRatidentical protein binding  IPIUnc13a (Rattus norvegicus)homodimerizationRGD 
Rims2Ratprotein binding enablesIPIUniProtKB:Q62768PMID:16732694IntAct 
Unc13aRatprotein binding enablesIPIUniProtKB:Q9JIS1PMID:16732694IntAct 
Rims2Ratprotein domain specific binding  IDA  RGD 
Unc13aRatprotein domain specific binding  IDA  RGD 
Rims2Ratprotein-containing complex binding  IDA heterodimerizationRGD 
Unc13aRatprotein-containing complex binding  IDA heterodimerizationRGD 

Objects Annotated

Genes (Rattus norvegicus)
Rims2  (regulating synaptic membrane exocytosis 2)
Unc13a  (unc-13 homolog A)


Additional Information