| Structural highlights
9dk5 is a 5 chain structure with sequence from Homo sapiens and Paraphysa scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.9Å |
| Ligands: | 9Z9, BMA, CLR, LPE, MAN, NAG, P3X, P5S, PCW, Y01 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
SCN8A_HUMAN Non-specific early-onset epileptic encephalopathy;Self-limited infantile epilepsy;Infantile convulsions and choreoathetosis;Autosomal dominant non-syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry.
Function
SCN8A_HUMAN Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradient (PubMed:24874546, PubMed:25239001, PubMed:25725044, PubMed:26900580, PubMed:29726066, PubMed:33245860, PubMed:36696443, PubMed:36823201). Contributes to neuronal excitability by regulating action potential threshold and propagation (PubMed:24874546, PubMed:25239001, PubMed:25725044, PubMed:26900580, PubMed:29726066, PubMed:33245860, PubMed:36696443, PubMed:36823201).[1] [2] [3] [4] [5] [6] [7] [8] More specifically expressed in non-neuronal cells, could play a role in sodium release from intracellular compartments and participate in the control of podosomes formation and macrophages adhesion and movement.[9]
References
- ↑ Estacion M, O'Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD, Meisler MH. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis. 2014 Sep;69:117-23. PMID:24874546 doi:10.1016/j.nbd.2014.05.017
- ↑ de Kovel CG, Meisler MH, Brilstra EH, van Berkestijn FM, van 't Slot R, van Lieshout S, Nijman IJ, O'Brien JE, Hammer MF, Estacion M, Waxman SG, Dib-Hajj SD, Koeleman BP. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014 Nov;108(9):1511-8. PMID:25239001 doi:10.1016/j.eplepsyres.2014.08.020
- ↑ Blanchard MG, Willemsen MH, Walker JB, Dib-Hajj SD, Waxman SG, Jongmans MC, Kleefstra T, van de Warrenburg BP, Praamstra P, Nicolai J, Yntema HG, Bindels RJ, Meisler MH, Kamsteeg EJ. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015 May;52(5):330-7. PMID:25725044 doi:10.1136/jmedgenet-2014-102813
- ↑ Wagnon JL, Barker BS, Hounshell JA, Haaxma CA, Shealy A, Moss T, Parikh S, Messer RD, Patel MK, Meisler MH. Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Ann Clin Transl Neurol. 2015 Dec 21;3(2):114-23. PMID:26900580 doi:10.1002/acn3.276
- ↑ Wagnon JL, Mencacci NE, Barker BS, Wengert ER, Bhatia KP, Balint B, Carecchio M, Wood NW, Patel MK, Meisler MH. Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat. 2018 Jul;39(7):965-969. PMID:29726066 doi:10.1002/humu.23547
- ↑ Fry AE, Marra C, Derrick AV, Pickrell WO, Higgins AT, Te Water Naude J, McClatchey MA, Davies SJ, Metcalfe KA, Tan HJ, Mohanraj R, Avula S, Williams D, Brady LI, Mesterman R, Tarnopolsky MA, Zhang Y, Yang Y, Wang X, Rees MI, Goldfarb M, Chung SK. Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy. Am J Hum Genet. 2021 Jan 7;108(1):176-185. PMID:33245860 doi:10.1016/j.ajhg.2020.10.017
- ↑ Fan X, Huang J, Jin X, Yan N. Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6. Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2220578120. PMID:36696443 doi:10.1073/pnas.2220578120
- ↑ Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D. Structure of human Na(V)1.6 channel reveals Na(+) selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. Nat Commun. 2023 Feb 23;14(1):1030. PMID:36823201 doi:10.1038/s41467-023-36766-9
- ↑ Carrithers MD, Chatterjee G, Carrithers LM, Offoha R, Iheagwara U, Rahner C, Graham M, Waxman SG. Regulation of podosome formation in macrophages by a splice variant of the sodium channel SCN8A. J Biol Chem. 2009 Mar 20;284(12):8114-26. PMID:19136557 doi:10.1074/jbc.M801892200
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