6e2f is a 5 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[CALM1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14.
Function
[TRPV6_HUMAN] Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11278579, PubMed:11248124 PubMed:15184369, PubMed:23612980). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.[UniProtKB:Q91WD2][1][2][3][4][5] [CALM1_HUMAN] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[6][7][8][9]
Publication Abstract from PubMed
Calcium (Ca(2+)) plays a major role in numerous physiological processes. Ca(2+) homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)-mediated Ca(2+)-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca(2+) overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient receptor potential vanilloid subfamily member 6) inactivated by CaM. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM carboxyl-terminal lobe plugs the channel through a unique cation-pi interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the pore's intracellular entrance. We propose a mechanism of CaM-mediated Ca(2+)-induced inactivation that can be explored for therapeutic design.
Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6.,Singh AK, McGoldrick LL, Twomey EC, Sobolevsky AI Sci Adv. 2018 Aug 15;4(8):eaau6088. doi: 10.1126/sciadv.aau6088. eCollection 2018, Aug. PMID:30116787[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium transport protein CaT1. Biochem Biophys Res Commun. 2000 Nov 19;278(2):326-32. doi:, 10.1006/bbrc.2000.3716. PMID:11097838 doi:http://dx.doi.org/10.1006/bbrc.2000.3716
↑ Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5. doi: 10.1073/pnas.051511398. PMID:11248124 doi:http://dx.doi.org/10.1073/pnas.051511398
↑ Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem. 2001 Jun 1;276(22):19461-8. doi: 10.1074/jbc.M009895200. Epub 2001, Feb 2. PMID:11278579 doi:http://dx.doi.org/10.1074/jbc.M009895200
↑ Bodding M, Flockerzi V. Ca2+ dependence of the Ca2+-selective TRPV6 channel. J Biol Chem. 2004 Aug 27;279(35):36546-52. doi: 10.1074/jbc.M404679200. Epub 2004, Jun 7. PMID:15184369 doi:http://dx.doi.org/10.1074/jbc.M404679200
↑ Fecher-Trost C, Wissenbach U, Beck A, Schalkowsky P, Stoerger C, Doerr J, Dembek A, Simon-Thomas M, Weber A, Wollenberg P, Ruppert T, Middendorff R, Maurer HH, Flockerzi V. The in vivo TRPV6 protein starts at a non-AUG triplet, decoded as methionine, upstream of canonical initiation at AUG. J Biol Chem. 2013 Jun 7;288(23):16629-44. doi: 10.1074/jbc.M113.469726. Epub 2013, Apr 23. PMID:23612980 doi:http://dx.doi.org/10.1074/jbc.M113.469726
↑ Tsang WY, Spektor A, Luciano DJ, Indjeian VB, Chen Z, Salisbury JL, Sanchez I, Dynlacht BD. CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability. Mol Biol Cell. 2006 Aug;17(8):3423-34. Epub 2006 Jun 7. PMID:16760425 doi:10.1091/mbc.E06-04-0371
↑ Reichow SL, Clemens DM, Freites JA, Nemeth-Cahalan KL, Heyden M, Tobias DJ, Hall JE, Gonen T. Allosteric mechanism of water-channel gating by Ca-calmodulin. Nat Struct Mol Biol. 2013 Jul 28. doi: 10.1038/nsmb.2630. PMID:23893133 doi:10.1038/nsmb.2630
↑ Boczek NJ, Gomez-Hurtado N, Ye D, Calvert ML, Tester DJ, Kryshtal D, Hwang HS, Johnson CN, Chazin WJ, Loporcaro CG, Shah M, Papez AL, Lau YR, Kanter R, Knollmann BC, Ackerman MJ. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi:, 10.1161/CIRCGENETICS.115.001323. Epub 2016 Mar 11. PMID:26969752 doi:http://dx.doi.org/10.1161/CIRCGENETICS.115.001323
↑ Yu CC, Ko JS, Ai T, Tsai WC, Chen Z, Rubart M, Vatta M, Everett TH 4th, George AL Jr, Chen PS. Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. Heart Rhythm. 2016 Aug;13(8):1716-23. doi: 10.1016/j.hrthm.2016.05.009. Epub 2016, May 7. PMID:27165696 doi:http://dx.doi.org/10.1016/j.hrthm.2016.05.009
↑ Singh AK, McGoldrick LL, Twomey EC, Sobolevsky AI. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Sci Adv. 2018 Aug 15;4(8):eaau6088. doi: 10.1126/sciadv.aau6088. eCollection 2018, Aug. PMID:30116787 doi:http://dx.doi.org/10.1126/sciadv.aau6088
