2CJT

Structural Basis for a Munc13-1 Homodimer - Munc13-1 - RIM Heterodimer Switch: C2-domains as Versatile Protein-Protein Interaction Modules

Summary for 2CJT

• Entry DOI: 10.2210/pdb2cjt/pdb
• Related: 1Y8F 2CJS
• Descriptor: UNC-13 HOMOLOG A, 1,2-ETHANEDIOL, FORMIC ACID, ... (4 entities in total)
• Functional Keywords: phorbol-ester binding, neurotransmitter release, rim, munc13, c2 domains, exocytosis, metal-binding, protein-protein interactions, zinc finger, synaptosome
• Biological source: RATTUS NORVEGICUS (RAT)
• Total number of polymer chains: 4
• Total formula weight: 60981.19

Authors

Lu, J.,Machius, M.,Dulubova, I.,Dai, H.,Sudhof, T.C.,Tomchick, D.R.,Rizo, J. (deposition date: 2006-04-06, release date: 2006-06-07, Last modification date: 2024-05-08)

Primary citation

Lu, J.,Machius, M.,Dulubova, I.,Dai, H.,Sudhof, T.C.,Tomchick, D.R.,Rizo, J.
Structural Basis for a Munc13-1 Dimeric to Munc13-1/Rim Heterodimer Switch
Plos Biol., 4:E192-, 2006

PubMed 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.

PubMed: 16732694
DOI: 10.1371/JOURNAL.PBIO.0040192

Experimental method

X-RAY DIFFRACTION (1.44 Å)