5v2q

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CaV beta2a subunit: CaV1.2 AID-CEN complex

Structural highlights

5v2q is a 2 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.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:8VY, CL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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.[4] [5] [6] [7] [8] [9]

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[10]

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

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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

Contents


PDB ID 5v2q

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