Structural Basis for a Munc13–1 Homodimer to Munc13–1/RIM Heterodimer Switch
- University of Texas Southwestern Medical Center, Dallas, TX (United States)
C2 domains are well characterized as Ca2+/phospholipid-binding modules, but little is known about how they mediate protein–protein interactions. In neurons, a Munc13–1 C2A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13–1 C2A 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 C2A-domain homodimer and the Munc13–1 C2A-domain/RIM ZF heterodimer at 1.44 Å and 1.78 Å resolution, respectively. The C2A domain adopts a bsandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded b-barrel. In contrast, heterodimerization involves the bottom tip of the C2A-domain β-sandwich and a C-terminal α-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 C2 domains as protein–protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States); University of Texas Southwestern Medical Center, Dallas, TX (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- Grant/Contract Number:
- W-31–109-ENG-38
- OSTI ID:
- 1627147
- Journal Information:
- PLoS Biology (Online), Vol. 4, Issue 7; ISSN 1545-7885
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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