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| - | [[Image:2cjt.gif|left|200px]]<br /><applet load="2cjt" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2cjt, resolution 1.44Å" /> | |
| - | '''STRUCTURAL BASIS FOR A MUNC13-1 HOMODIMER- MUNC13-1- RIM HETERODIMER SWITCH: C2-DOMAINS AS VERSATILE PROTEIN-PROTEIN INTERACTION MODULES'''<br /> | |
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| - | ==Overview== | + | ==Structural Basis for a Munc13-1 Homodimer - Munc13-1 - RIM Heterodimer Switch: C2-domains as Versatile Protein-Protein Interaction Modules== |
| - | 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. | + | <StructureSection load='2cjt' size='340' side='right'caption='[[2cjt]], [[Resolution|resolution]] 1.44Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2cjt]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CJT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CJT FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.44Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2cjt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cjt OCA], [https://pdbe.org/2cjt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cjt RCSB], [https://www.ebi.ac.uk/pdbsum/2cjt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cjt ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/UN13A_RAT 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.<ref>PMID:9697857</ref> <ref>PMID:11343654</ref> <ref>PMID:11792326</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == 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. |
| | | | |
| - | ==About this Structure==
| + | 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<ref>PMID:16732694</ref> |
| - | 2CJT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=EDO:'>EDO</scene> and <scene name='pdbligand=FMT:'>FMT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Site: <scene name='pdbsite=AC1:Fmt+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CJT OCA].
| + | |
| | | | |
| - | ==Reference== | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 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 Jun;4(7):e192. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16732694 16732694]
| + | </div> |
| | + | <div class="pdbe-citations 2cjt" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Rattus norvegicus]] | | [[Category: Rattus norvegicus]] |
| - | [[Category: Single protein]]
| + | [[Category: Dai H]] |
| - | [[Category: Dai, H.]] | + | [[Category: Dulubova I]] |
| - | [[Category: Dulubova, I.]] | + | [[Category: Lu J]] |
| - | [[Category: Lu, J.]] | + | [[Category: Machius M]] |
| - | [[Category: Machius, M.]] | + | [[Category: Rizo J]] |
| - | [[Category: Rizo, J.]] | + | [[Category: Sudhof TC]] |
| - | [[Category: Sudhof, T.C.]] | + | [[Category: Tomchick DR]] |
| - | [[Category: Tomchick, D.R.]] | + | |
| - | [[Category: EDO]]
| + | |
| - | [[Category: FMT]]
| + | |
| - | [[Category: alternative splicing]]
| + | |
| - | [[Category: c2 domains]]
| + | |
| - | [[Category: coiled coil]]
| + | |
| - | [[Category: exocytosis]]
| + | |
| - | [[Category: metal-binding]]
| + | |
| - | [[Category: munc13]]
| + | |
| - | [[Category: neurotransmitter release]]
| + | |
| - | [[Category: phorbol-ester binding]]
| + | |
| - | [[Category: protein-protein interactions]]
| + | |
| - | [[Category: rim]]
| + | |
| - | [[Category: synaptosome]]
| + | |
| - | [[Category: zinc]]
| + | |
| - | [[Category: zinc finger]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb 3 10:36:12 2008''
| + | |
| Structural highlights
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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