| Structural highlights
6but is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | CALM1, CALM, CAM, CAM1 (HUMAN), SCN2A, NAC2, SCN2A1, SCN2A2 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[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. [SCN2A_HUMAN] Defects in SCN2A are the cause of seizures, benign familial infantile type 3 (BFIS3) [MIM:607745]. An autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae.[1] [2] [3] [4] Defects in SCN2A are the cause of epileptic encephalopathy early infantile type 11 (EIEE11) [MIM:613721]. EIEE11 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities.[5] [6]
Function
[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).[7] [8] [9] [10] [SCN2A_HUMAN] Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient.
Publication Abstract from PubMed
Neuronal voltage-gated sodium channel NaV1.2 C-terminal domain (CTD) binds calmodulin (CaM) constitutively at its IQ motif. A solution structure (6BUT) and other NMR evidence showed that the CaM N domain (CaMN) is structurally independent of the C-domain (CaMC) whether CaM is bound to the NaV1.2IQp (1,901-1,927) or NaV1.2CTD (1,777-1,937) with or without calcium. However, in the CaM + NaV1.2CTD complex, the Ca(2+) affinity of CaMN was more favorable than in free CaM, while Ca(2+) affinity for CaMC was weaker than in the CaM + NaV1.2IQp complex. The CTD EF-like (EFL) domain allosterically widened the energetic gap between CaM domains. Cardiomyopathy-associated CaM mutants (N53I(N54I), D95V(D96V), A102V(A103V), E104A(E105A), D129G(D130G), and F141L(F142L)) all bound the NaV1.2 IQ motif favorably under resting (apo) conditions and bound calcium normally at CaMN sites. However, only N53I and A102V bound calcium at CaMC sites at [Ca(2+)] < 100 muM. Thus, they are expected to respond like wild-type CaM to Ca(2+) spikes in excitable cells.
NaV1.2 EFL domain allosterically enhances Ca(2+) binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD.,Mahling R, Hovey L, Isbell HM, Marx DC, Miller MS, Kilpatrick AM, Weaver LD, Yoder JB, Kim EH, Andresen CNJ, Li S, Shea MA Structure. 2021 Mar 23. pii: S0969-2126(21)00075-7. doi:, 10.1016/j.str.2021.03.002. PMID:33770503[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, Mitsudome A, Kaneko S, Montal M, Nagata K, Hirose S, Yamakawa K. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6384-9. PMID:11371648 doi:10.1073/pnas.111065098
- ↑ Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, Shevell M, Mercho S, Seni MH, Guiot MC, Mulley JC, Berkovic SF, Scheffer IE. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002 Sep 14;360(9336):851-2. PMID:12243921 doi:10.1016/S0140-6736(02)09968-3
- ↑ Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, Yamamoto T, Mulley JC, Zara F, Scheffer IE. Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol. 2004 Apr;55(4):550-7. PMID:15048894 doi:10.1002/ana.20029
- ↑ Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, Jordanova A, Ala-Mello S, Bellan-Koch A, Blazevic D, Schubert S, Thomas EA, Petrou S, Becker AJ, De Jonghe P, Lerche H. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain. 2010 May;133(Pt 5):1403-14. doi: 10.1093/brain/awq057. Epub 2010 Apr 5. PMID:20371507 doi:10.1093/brain/awq057
- ↑ Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, Yamakawa K. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology. 2009 Sep 29;73(13):1046-53. doi: 10.1212/WNL.0b013e3181b9cebc. PMID:19786696 doi:10.1212/WNL.0b013e3181b9cebc
- ↑ Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, Bellan-Koch A, Petrou S, Ahonen VE, Lerche H, Lehesjoki AE. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology. 2010 Oct 19;75(16):1454-8. doi: 10.1212/WNL.0b013e3181f8812e. PMID:20956790 doi:10.1212/WNL.0b013e3181f8812e
- ↑ 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:https://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:https://dx.doi.org/10.1016/j.hrthm.2016.05.009
- ↑ Mahling R, Hovey L, Isbell HM, Marx DC, Miller MS, Kilpatrick AM, Weaver LD, Yoder JB, Kim EH, Andresen CNJ, Li S, Shea MA. NaV1.2 EFL domain allosterically enhances Ca(2+) binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD. Structure. 2021 Mar 23. pii: S0969-2126(21)00075-7. doi:, 10.1016/j.str.2021.03.002. PMID:33770503 doi:https://dx.doi.org/10.1016/j.str.2021.03.002
|
