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| | <StructureSection load='5v2q' size='340' side='right'caption='[[5v2q]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='5v2q' size='340' side='right'caption='[[5v2q]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5v2q]] is a 2 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=5V2Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V2Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5v2q]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V2Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V2Q FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8VY:1,3-bis(bromomethyl)benzene'>8VY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v2p|5v2p]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8VY:1,3-bis(bromomethyl)benzene'>8VY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Cacnb2, Cacnlb2 ([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=5v2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v2q OCA], [https://pdbe.org/5v2q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v2q RCSB], [https://www.ebi.ac.uk/pdbsum/5v2q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v2q 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=5v2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v2q OCA], [http://pdbe.org/5v2q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v2q RCSB], [http://www.ebi.ac.uk/pdbsum/5v2q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v2q ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:[http://omim.org/entry/601005 601005]]. TS is a disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.<ref>PMID:15454078</ref> <ref>PMID:15863612</ref> Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRGDA3) [MIM:[http://omim.org/entry/611875 611875]]. A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.<ref>PMID:17224476</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CACB2_RAT CACB2_RAT]] The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting (By similarity).<ref>PMID:1370480</ref> <ref>PMID:11604404</ref> <ref>PMID:12042350</ref> [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function.<ref>PMID:8392192</ref> <ref>PMID:7737988</ref> <ref>PMID:9013606</ref> <ref>PMID:9607315</ref> <ref>PMID:12176756</ref> <ref>PMID:17071743</ref> | + | [https://www.uniprot.org/uniprot/CACB2_RAT CACB2_RAT] The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting (By similarity).<ref>PMID:1370480</ref> <ref>PMID:11604404</ref> <ref>PMID:12042350</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Campiglio, M]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Degrado, W F]] | + | [[Category: Campiglio M]] |
| - | [[Category: Findeisen, F]] | + | [[Category: Degrado WF]] |
| - | [[Category: Flucher, B]] | + | [[Category: Findeisen F]] |
| - | [[Category: Jo, H]] | + | [[Category: Flucher B]] |
| - | [[Category: Minor, D L]] | + | [[Category: Jo H]] |
| - | [[Category: Pope, L]] | + | [[Category: Minor DL]] |
| - | [[Category: Rumpf, C H]] | + | [[Category: Pope L]] |
| - | [[Category: Calcium]]
| + | [[Category: Rumpf CH]] |
| - | [[Category: Ion channel]]
| + | |
| - | [[Category: Signaling]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
CACB2_RAT The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting (By similarity).[1] [2] [3]
Publication Abstract from PubMed
For many voltage-gated ion channels (VGICs), creation of a properly functioning ion channel requires the formation of specific protein-protein interactions between the transmembrane pore-forming subunits and cystoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta-xylyl (m-xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore-forming subunit alpha-interaction domain (AID) and cytoplasmic beta-subunit (CaVbeta). We show using circular dichroism spectroscopy, X-ray crystallography, and isothermal titration calorimetry that the m-xylyl staples enhance AID helix formation are structurally compatible with native-like AID:CaVbeta interactions and reduce the entropic penalty associated with AID binding to CaVbeta. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaValpha1:CaVbeta interaction that modulate CaV function in an CaVbeta isoform-selective manner. Together, our studies provide a proof-of-concept demonstration of the use of protein-protein interaction inhibitors to control VGIC function and point to strategies for improved AID-based CaV modulator design.
Stapled Voltage-Gated Calcium Channel (CaV) alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.,Findeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL Jr ACS Chem Neurosci. 2017 Jun 21;8(6):1313-1326. doi: 10.1021/acschemneuro.6b00454., Epub 2017 Mar 17. PMID:28278376[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Perez-Reyes E, Castellano A, Kim HS, Bertrand P, Baggstrom E, Lacerda AE, Wei XY, Birnbaumer L. Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel. J Biol Chem. 1992 Jan 25;267(3):1792-7. PMID:1370480
- ↑ Yamada Y, Nagashima M, Tsutsuura M, Kobayashi T, Seki S, Makita N, Horio Y, Tohse N. Cloning of a functional splice variant of L-type calcium channel beta 2 subunit from rat heart. J Biol Chem. 2001 Dec 14;276(50):47163-70. Epub 2001 Oct 16. PMID:11604404 doi:10.1074/jbc.M108049200
- ↑ Colecraft HM, Alseikhan B, Takahashi SX, Chaudhuri D, Mittman S, Yegnasubramanian V, Alvania RS, Johns DC, Marban E, Yue DT. Novel functional properties of Ca(2+) channel beta subunits revealed by their expression in adult rat heart cells. J Physiol. 2002 Jun 1;541(Pt 2):435-52. PMID:12042350
- ↑ Findeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL Jr. Stapled Voltage-Gated Calcium Channel (CaV) alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function. ACS Chem Neurosci. 2017 Jun 21;8(6):1313-1326. doi: 10.1021/acschemneuro.6b00454., Epub 2017 Mar 17. PMID:28278376 doi:http://dx.doi.org/10.1021/acschemneuro.6b00454
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