2CJT: Structural Basis For A Munc13-1 Dimeric - Munc13-1 - Rim Heterodimer Switch: C2-Domains As Versatile Protein- Protein Interaction Modules

Citation:
Abstract
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.
PDB ID: 2CJTDownload
MMDB ID: 86985
PDB Deposition Date: 2006/4/6
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 1.44  Å
Source Organism:
Similar Structures:
Biological Unit for 2CJT: dimeric; determined by author and by software (PQS)
Molecular Components in 2CJT
Label Count Molecule
Proteins (2 molecules)
2
Unc-13 Homolog a(Gene symbol: Unc13a)
Molecule annotation
Chemicals (17 molecules)
1
11
2
6
* Click molecule labels to explore molecular sequence information.

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