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

Jun Lu, Mischa Machius, Irina Dulubova, Han Dai, Thomas C. Südhof, Diana R Tomchick, Jose Rizo-Rey

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish (US)
JournalPLoS Biology
Volume4
Issue number7
DOIs
StatePublished - Jun 2006

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Reaction injection molding
zinc finger motif
Zinc Fingers
Switches
protein-protein interactions
sandwiches
X-ray diffraction
nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Zinc
Protein Interaction Domains and Motifs
Proteins
Synaptic Vesicles
X Ray Crystallography
Plasticity
crystal structure
X-Ray Diffraction
Phospholipids
phospholipids
neurons

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. / Lu, Jun; Machius, Mischa; Dulubova, Irina; Dai, Han; Südhof, Thomas C.; Tomchick, Diana R; Rizo-Rey, Jose.

In: PLoS Biology, Vol. 4, No. 7, 06.2006.

Research output: Contribution to journalArticle

Lu, Jun ; Machius, Mischa ; Dulubova, Irina ; Dai, Han ; Südhof, Thomas C. ; Tomchick, Diana R ; Rizo-Rey, Jose. / Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. In: PLoS Biology. 2006 ; Vol. 4, No. 7.
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