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| | <StructureSection load='4wee' size='340' side='right'caption='[[4wee]], [[Resolution|resolution]] 0.89Å' scene=''> | | <StructureSection load='4wee' size='340' side='right'caption='[[4wee]], [[Resolution|resolution]] 0.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wee]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WEE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WEE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wee]] is a 1 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=4WEE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WEE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.891Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1rsy|1rsy]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Syt1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=4wee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wee OCA], [https://pdbe.org/4wee PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wee RCSB], [https://www.ebi.ac.uk/pdbsum/4wee PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wee ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wee OCA], [http://pdbe.org/4wee PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wee RCSB], [http://www.ebi.ac.uk/pdbsum/4wee PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wee ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SYT1_RAT SYT1_RAT]] May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. | + | [https://www.uniprot.org/uniprot/SYT1_RAT SYT1_RAT] May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | C2 domains are regulatory sequence motifs that occur widely in nature. Synaptotagmin I, a synaptic vesicle protein involved in the Ca2+ regulation of exocytosis, contains two C2 domains, the first of which acts as a Ca2+ sensor. We now describe the three-dimensional structure of this C2 domain at 1.9 A resolution in both the Ca(2+)-bound and Ca(2+)-free forms. The C2 polypeptide forms an eight-stranded beta sandwich constructed around a conserved four-stranded motif designated as a C2 key. Ca2+ binds in a cup-shaped depression between two polypeptide loops located at the N- and C-termini of the C2-key motif.
| + | Synaptotagmin-1 (syt1) functions as the Ca(2+)-dependent sensor that triggers the rapid and synchronous release of neurotransmitters from neurotransmitter-containing vesicles during neuronal exocytosis. The syt1 protein has two homologous tandem C2 domains that interact with phospholipids in a Ca(2+)-dependent manner. Despite the crucial role of syt1 in exocytosis, the precise interactions between Ca(2+), syt1, and phospholipids are not fully understood. In a study involving recessive lethal mutations in the syt1 gene, a specific mutation named AD3 was generated in Drosophila syt1, resulting in a significant reduction in Ca(2+)-dependent exocytosis. Further investigation revealed that the AD3 mutation was a missense mutation located in a conserved consensus sequence within the C2B domain of Drosophila syt1. However, the biophysical impact of the AD3 mutation had not been analyzed. Our study uses x-ray crystallography, isothermal titration calorimetry, thermodynamic analysis, and molecular dynamics simulation to show that the primary defect caused by the AD3 mutation in the syt1 protein is reduced thermodynamic stability. This instability alters the population of Ca(2+)-receptive states, leading to two major consequences: decreased affinity for calcium ions and compromised stabilization of the domain normally enhanced by Ca(2+). We conclude that this conserved residue acts as a structural constraint, delimiting the movement of loop 3 within the pocket and ultimately influencing the affinity of the calcium ion binding with the C2 domain. |
| | | | |
| - | Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold.,Sutton RB, Davletov BA, Berghuis AM, Sudhof TC, Sprang SR Cell. 1995 Mar 24;80(6):929-38. PMID:7697723<ref>PMID:7697723</ref>
| + | The AD3 locus of synaptotagmin-1 C2 domains modulates domain stability.,Dominguez MJ, Bui AA, Villarreal J, Snow A, Karmakar S, Harsini FM, Rock PJ, Rice AM, Fuson KL, Sutton RB Biophys J. 2024 Nov 22:S0006-3495(24)00718-5. doi: 10.1016/j.bpj.2024.11.009. PMID:39578407<ref>PMID:39578407</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
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| | ==See Also== | | ==See Also== |
| - | *[[Synaptotagmin|Synaptotagmin]] | + | *[[Synaptotagmin 3D structures|Synaptotagmin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Fuson, K L]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Sutton, R B]] | + | [[Category: Fuson KL]] |
| - | [[Category: Beta-sandwich]] | + | [[Category: Sutton RB]] |
| - | [[Category: C2 domain]]
| + | |
| - | [[Category: Ca2+]]
| + | |
| - | [[Category: Metal binding protein]]
| + | |
| - | [[Category: Synaptotagmin]]
| + | |
| Structural highlights
Function
SYT1_RAT May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2.
Publication Abstract from PubMed
Synaptotagmin-1 (syt1) functions as the Ca(2+)-dependent sensor that triggers the rapid and synchronous release of neurotransmitters from neurotransmitter-containing vesicles during neuronal exocytosis. The syt1 protein has two homologous tandem C2 domains that interact with phospholipids in a Ca(2+)-dependent manner. Despite the crucial role of syt1 in exocytosis, the precise interactions between Ca(2+), syt1, and phospholipids are not fully understood. In a study involving recessive lethal mutations in the syt1 gene, a specific mutation named AD3 was generated in Drosophila syt1, resulting in a significant reduction in Ca(2+)-dependent exocytosis. Further investigation revealed that the AD3 mutation was a missense mutation located in a conserved consensus sequence within the C2B domain of Drosophila syt1. However, the biophysical impact of the AD3 mutation had not been analyzed. Our study uses x-ray crystallography, isothermal titration calorimetry, thermodynamic analysis, and molecular dynamics simulation to show that the primary defect caused by the AD3 mutation in the syt1 protein is reduced thermodynamic stability. This instability alters the population of Ca(2+)-receptive states, leading to two major consequences: decreased affinity for calcium ions and compromised stabilization of the domain normally enhanced by Ca(2+). We conclude that this conserved residue acts as a structural constraint, delimiting the movement of loop 3 within the pocket and ultimately influencing the affinity of the calcium ion binding with the C2 domain.
The AD3 locus of synaptotagmin-1 C2 domains modulates domain stability.,Dominguez MJ, Bui AA, Villarreal J, Snow A, Karmakar S, Harsini FM, Rock PJ, Rice AM, Fuson KL, Sutton RB Biophys J. 2024 Nov 22:S0006-3495(24)00718-5. doi: 10.1016/j.bpj.2024.11.009. PMID:39578407[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dominguez MJ, Bui AA, Villarreal J, Snow A, Karmakar S, Harsini FM, Rock PJ, Rice AM, Fuson KL, Sutton RB. The AD3 locus of synaptotagmin-1 C2 domains modulates domain stability. Biophys J. 2024 Nov 22:S0006-3495(24)00718-5. PMID:39578407 doi:10.1016/j.bpj.2024.11.009
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