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PMID: 16732694 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

PLoS biology ·Vol. 4 ·No. 7 ·2006-07-00 ·Pages e192

Lu J, Machius M, Dulubova I, Dai H, Südhof TC, Tomchick DR, Rizo J

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.

MeSH Terms
Amino Acid Sequence Animals Crystallography, X-Ray/methods Dimerization Magnetic Resonance Spectroscopy/methods Models, Molecular Molecular Sequence Data Nerve Tissue Proteins/chemistry,metabolism,physiology Protein Binding Protein Conformation Protein Interaction Mapping Protein Structure, Tertiary Rats Sequence Alignment Synaptic Vesicles/metabolism Zinc Fingers
Chemicals
Nerve Tissue Proteins Rims2 protein, rat Unc13a protein, rat
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lu Jun
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Machius Mischa
Dulubova Irina
Dai Han
Südhof Thomas C
Tomchick Diana R
Rizo Josep
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Article Info
Journal
PLoS biology
Abbr.
PLoS Biol
ISSN
1545-7885
DOI
10.1371/journal.pbio.0040192
Published
2006-07-00
Pages
e192
Language
English
Region
United States
NLM ID
101183755
PMCID
PMC1472246
Subset
IM
Grants
NINDS NIH HHS · R01 NS040944 · United States
NINDS NIH HHS · NS40944 · United States
Databases
PDB
1DJX, 2CJS, 2CJT
Corrections
CommentIn
PMID: 20076599
External Links
PubMed source DOI: 10.1371/journal.pbio.0040192 PMC Full Text View journal details
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