| Structural highlights
1t0j is a 3 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 1toh |
| Gene: | CACNB2A (Rattus norvegicus), CACNA1C, CACNL1A1, CCHL1A1, CACH2, CACN2 (Homo sapiens) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[CAC1C_HUMAN] Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM: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.[1] [2] Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRGDA3) [MIM: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.[3]
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).[4] [5] [6] [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.[7] [8] [9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Voltage-gated calcium channels (Ca(V)s) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration. An essential Ca(V) intracellular protein, the beta-subunit (Ca(V)beta), binds a conserved domain (the alpha-interaction domain, AID) between transmembrane domains I and II of the pore-forming alpha(1) subunit and profoundly affects multiple channel properties such as voltage-dependent activation, inactivation rates, G-protein modulation, drug sensitivity and cell surface expression. Here, we report the high-resolution crystal structures of the Ca(V)beta2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the beta-interaction domain (BID), formed the AID-binding site; however, this region is largely buried in the Ca(V)beta core and is unavailable for protein-protein interactions. The structure of the AID-Ca(V)beta2a complex shows instead that Ca(V)beta2a engages the AID through an extensive, conserved hydrophobic cleft (named the alpha-binding pocket, ABP). The ABP-AID interaction positions one end of the Ca(V)beta near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca(V) inactivation. Together, these data suggest that Ca(V)betas influence Ca(V) gating by direct modulation of IS6 movement within the channel pore.
Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain.,Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr Nature. 2004 Jun 10;429(6992):671-5. Epub 2004 May 12. PMID:15141227[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004 Oct 1;119(1):19-31. PMID:15454078 doi:10.1016/j.cell.2004.09.011
- ↑ Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8089-96; discussion 8086-8. Epub, 2005 Apr 29. PMID:15863612 doi:10.1073/pnas.0502506102
- ↑ Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP Jr, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haissaguerre M, Schimpf R, Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007 Jan 30;115(4):442-9. Epub 2007 Jan 15. PMID:17224476 doi:10.1161/CIRCULATIONAHA.106.668392
- ↑ 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
- ↑ Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B, Sinke RJ, Weghuis DO, Klockner U, Wakamori M, et al.. Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6228-32. PMID:8392192
- ↑ Soldatov NM, Bouron A, Reuter H. Different voltage-dependent inhibition by dihydropyridines of human Ca2+ channel splice variants. J Biol Chem. 1995 May 5;270(18):10540-3. PMID:7737988
- ↑ Soldatov NM, Zuhlke RD, Bouron A, Reuter H. Molecular structures involved in L-type calcium channel inactivation. Role of the carboxyl-terminal region encoded by exons 40-42 in alpha1C subunit in the kinetics and Ca2+ dependence of inactivation. J Biol Chem. 1997 Feb 7;272(6):3560-6. PMID:9013606
- ↑ Zuhlke RD, Bouron A, Soldatov NM, Reuter H. Ca2+ channel sensitivity towards the blocker isradipine is affected by alternative splicing of the human alpha1C subunit gene. FEBS Lett. 1998 May 8;427(2):220-4. PMID:9607315
- ↑ Lyford GL, Strege PR, Shepard A, Ou Y, Ermilov L, Miller SM, Gibbons SJ, Rae JL, Szurszewski JH, Farrugia G. alpha(1C) (Ca(V)1.2) L-type calcium channel mediates mechanosensitive calcium regulation. Am J Physiol Cell Physiol. 2002 Sep;283(3):C1001-8. PMID:12176756 doi:10.1152/ajpcell.00140.2002
- ↑ Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM. Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel alpha1C subunit. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):17024-9. Epub 2006 Oct 27. PMID:17071743 doi:0606539103
- ↑ Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr. Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature. 2004 Jun 10;429(6992):671-5. Epub 2004 May 12. PMID:15141227 doi:http://dx.doi.org/10.1038/nature02588
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