2cjt

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

Structural highlights

2cjt is a 4 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.44Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UN13A_RAT Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Also involved in secretory granule priming in insulin secretion.^[1] ^[2] ^[3]

Publication Abstract from PubMed

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.

Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.,Lu J, Machius M, Dulubova I, Dai H, Sudhof TC, Tomchick DR, Rizo J PLoS Biol. 2006 Jul;4(7):e192. PMID:16732694^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Sudhof TC, Rettig J, Brose N. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998 Jul;21(1):123-36. PMID:9697857
↑ Betz A, Thakur P, Junge HJ, Ashery U, Rhee JS, Scheuss V, Rosenmund C, Rettig J, Brose N. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron. 2001 Apr;30(1):183-96. PMID:11343654
↑ Rhee JS, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I, Hesse D, Sudhof TC, Takahashi M, Rosenmund C, Brose N. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002 Jan 11;108(1):121-33. PMID:11792326
↑ Lu J, Machius M, Dulubova I, Dai H, Sudhof TC, Tomchick DR, Rizo J. Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biol. 2006 Jul;4(7):e192. PMID:16732694 doi:10.1371/journal.pbio.0040192

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OCA

[1] Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Sudhof TC, Rettig J, Brose N. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998 Jul;21(1):123-36. PMID:9697857

[2] Betz A, Thakur P, Junge HJ, Ashery U, Rhee JS, Scheuss V, Rosenmund C, Rettig J, Brose N. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron. 2001 Apr;30(1):183-96. PMID:11343654

[3] Rhee JS, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I, Hesse D, Sudhof TC, Takahashi M, Rosenmund C, Brose N. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002 Jan 11;108(1):121-33. PMID:11792326

[4] Lu J, Machius M, Dulubova I, Dai H, Sudhof TC, Tomchick DR, Rizo J. Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biol. 2006 Jul;4(7):e192. PMID:16732694 doi:10.1371/journal.pbio.0040192

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