ID SCN2A_RAT Reviewed; 2005 AA.
AC P04775;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-1987, sequence version 1.
DT 24-JAN-2024, entry version 185.
DE RecName: Full=Sodium channel protein type 2 subunit alpha {ECO:0000305};
DE AltName: Full=Sodium channel protein brain II subunit alpha;
DE AltName: Full=Sodium channel protein type II subunit alpha;
DE AltName: Full=Voltage-gated sodium channel subunit alpha Nav1.2;
GN Name=Scn2a {ECO:0000312|RGD:3632}; Synonyms=Scn2a1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3754035; DOI=10.1038/320188a0;
RA Noda M., Ikeda T., Kayano T., Suzuki H., Takeshima H., Kurasaki M.,
RA Takahashi H., Numa S.;
RT "Existence of distinct sodium channel messenger RNAs in rat brain.";
RL Nature 320:188-192(1986).
RN [2]
RP PHOSPHORYLATION AT SER-1506, AND MUTAGENESIS OF SER-1506.
RX PubMed=1658937; DOI=10.1126/science.1658937;
RA West J.W., Numann R., Murphy B.J., Scheuer T., Catterall W.A.;
RT "A phosphorylation site in the Na+ channel required for modulation by
RT protein kinase C.";
RL Science 254:866-868(1991).
RN [3]
RP PHOSPHORYLATION AT SER-554; SER-573; SER-576 AND SER-1506.
RX PubMed=1322892; DOI=10.1016/s0021-9258(18)41976-x;
RA Murphy B.J., Catterall W.A.;
RT "Phosphorylation of purified rat brain Na+ channel reconstituted into
RT phospholipid vesicles by protein kinase C.";
RL J. Biol. Chem. 267:16129-16134(1992).
RN [4]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=10827969; DOI=10.1016/s0006-3495(00)76829-9;
RA Planells-Cases R., Caprini M., Zhang J., Rockenstein E.M., Rivera R.R.,
RA Murre C., Masliah E., Montal M.;
RT "Neuronal death and perinatal lethality in voltage-gated sodium channel
RT alpha(II)-deficient mice.";
RL Biophys. J. 78:2878-2891(2000).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF 879-GLY--LEU-881.
RX PubMed=11166117; DOI=10.1016/s0306-4522(00)00479-6;
RA Kearney J.A., Plummer N.W., Smith M.R., Kapur J., Cummins T.R.,
RA Waxman S.G., Goldin A.L., Meisler M.H.;
RT "A gain-of-function mutation in the sodium channel gene Scn2a results in
RT seizures and behavioral abnormalities.";
RL Neuroscience 102:307-317(2001).
RN [6]
RP INTERACTION WITH NEDD4L, POSSIBLE UBIQUITINATION, AND MUTAGENESIS OF
RP TYR-1975.
RX PubMed=15548568; DOI=10.1152/ajpcell.00460.2004;
RA Rougier J.-S., van Bemmelen M.X., Bruce M.C., Jespersen T., Gavillet B.,
RA Apotheloz F., Cordonier S., Staub O., Rotin D., Abriel H.;
RT "Molecular determinants of voltage-gated sodium channel regulation by the
RT Nedd4/Nedd4-like proteins.";
RL Am. J. Physiol. 288:C692-C701(2005).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1963, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT regulation of aquaporin-2 phosphorylation at two sites.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN [8]
RP INTERACTION WITH SCORPION TOXIN BMK M1, AND MUTAGENESIS OF GLU-1613.
RX PubMed=20678086; DOI=10.1042/bj20100517;
RA He H., Liu Z., Dong B., Zhou J., Zhu H., Ji Y.;
RT "Molecular determination of selectivity of the site 3 modulator (BmK I) to
RT sodium channels in the CNS: a clue to the importance of Nav1.6 in BmK I-
RT induced neuronal hyperexcitability.";
RL Biochem. J. 431:289-298(2010).
RN [9]
RP PHOSPHORYLATION AT SER-4; SER-468; SER-471; SER-484; SER-528; SER-554;
RP SER-610; SER-623; SER-687; SER-688; SER-721; SER-1930; THR-1966 AND
RP SER-1971.
RX PubMed=20131913; DOI=10.1021/pr901171q;
RA Berendt F.J., Park K.S., Trimmer J.S.;
RT "Multisite phosphorylation of voltage-gated sodium channel alpha subunits
RT from rat brain.";
RL J. Proteome Res. 9:1976-1984(2010).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484; SER-526; SER-528;
RP SER-531; SER-553; SER-554; SER-558; SER-589; SER-721 AND THR-1943, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [11]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, DISULFIDE
RP BOND, AND INTERACTION WITH SCN4B.
RX PubMed=24297919; DOI=10.1073/pnas.1314557110;
RA Gilchrist J., Das S., Van Petegem F., Bosmans F.;
RT "Crystallographic insights into sodium-channel modulation by the beta4
RT subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E5016-E5024(2013).
RN [12]
RP MUTAGENESIS OF CYS-910, INTERACTION WITH THE CONOTOXIN GVIIJ, AND DISULFIDE
RP BOND.
RX PubMed=24497506; DOI=10.1073/pnas.1324189111;
RA Gajewiak J., Azam L., Imperial J., Walewska A., Green B.R.,
RA Bandyopadhyay P.K., Raghuraman S., Ueberheide B., Bern M., Zhou H.M.,
RA Minassian N.A., Hagan R.H., Flinspach M., Liu Y., Bulaj G., Wickenden A.D.,
RA Olivera B.M., Yoshikami D., Zhang M.M.;
RT "A disulfide tether stabilizes the block of sodium channels by the
RT conotoxin muO[section sign]-GVIIJ.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:2758-2763(2014).
RN [13]
RP MUTAGENESIS OF PHE-385.
RX PubMed=26039939; DOI=10.1021/acs.biochem.5b00390;
RA Zhang M.M., Gajewiak J., Azam L., Bulaj G., Olivera B.M., Yoshikami D.;
RT "Probing the redox states of sodium channel cysteines at the binding site
RT of muO[section sign]-conotoxin GVIIJ.";
RL Biochemistry 54:3911-3920(2015).
RN [14]
RP STRUCTURE BY NMR OF 1474-1526, FUNCTION, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF PHE-1489.
RX PubMed=9893979; DOI=10.1021/bi9823380;
RA Rohl C.A., Boeckman F.A., Baker C., Scheuer T., Catterall W.A.,
RA Klevit R.E.;
RT "Solution structure of the sodium channel inactivation gate.";
RL Biochemistry 38:855-861(1999).
RN [15]
RP STRUCTURE BY NMR OF 1901-1927 IN COMPLEX WITH CALM, AND INTERACTION WITH
RP CALM.
RX PubMed=21439835; DOI=10.1016/j.str.2011.02.009;
RA Feldkamp M.D., Yu L., Shea M.A.;
RT "Structural and energetic determinants of apo calmodulin binding to the IQ
RT motif of the Na(V)1.2 voltage-dependent sodium channel.";
RL Structure 19:733-747(2011).
RN [16]
RP SUBUNIT, AND DISULFIDE BOND.
RX PubMed=26894959; DOI=10.7554/elife.10960;
RA Das S., Gilchrist J., Bosmans F., Van Petegem F.;
RT "Binary architecture of the Nav1.2-beta2 signaling complex.";
RL Elife 5:0-0(2016).
RN [17]
RP FUNCTION, TRANSPORTER ACTIVITY, SUMOYLATION AT LYS-38, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF LYS-38.
RX PubMed=28029095; DOI=10.7554/elife.20054;
RA Plant L.D., Marks J.D., Goldstein S.A.;
RT "SUMOylation of NaV1.2 channels mediates the early response to acute
RT hypoxia in central neurons.";
RL Elife 5:0-0(2016).
CC -!- FUNCTION: Mediates the voltage-dependent sodium ion permeability of
CC excitable membranes. Assuming opened or closed conformations in
CC response to the voltage difference across the membrane, the protein
CC forms a sodium-selective channel through which Na(+) ions may pass in
CC accordance with their electrochemical gradient. Implicated in the
CC regulation of hippocampal replay occurring within sharp wave ripples
CC (SPW-R) important for memory (By similarity).
CC {ECO:0000250|UniProtKB:B1AWN6, ECO:0000269|PubMed:24297919,
CC ECO:0000269|PubMed:28029095, ECO:0000269|PubMed:9893979}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Na(+)(in) = Na(+)(out); Xref=Rhea:RHEA:34963,
CC ChEBI:CHEBI:29101; Evidence={ECO:0000269|PubMed:24297919,
CC ECO:0000269|PubMed:28029095};
CC -!- SUBUNIT: Heterooligomer of a large alpha subunit and a smaller beta
CC subunit. Heterooligomer with SCN2B or SCN4B; disulfide-linked
CC (PubMed:26894959). Heterooligomer with SCN1B or SCN3B; non-covalently
CC linked. Interacts with NEDD4L. Interacts with CALM. Interacts with
CC TMEM233 (By similarity). Interacts with the conotoxin GVIIJ
CC (PubMed:24497506). Interacts with the scorpion toxin BMK M1
CC (PubMed:20678086). {ECO:0000250|UniProtKB:Q99250,
CC ECO:0000269|PubMed:15548568, ECO:0000269|PubMed:21439835,
CC ECO:0000269|PubMed:24297919, ECO:0000269|PubMed:24497506,
CC ECO:0000269|PubMed:26894959}.
CC -!- INTERACTION:
CC P04775; P21707: Syt1; NbExp=2; IntAct=EBI-2619448, EBI-458098;
CC P04775; P07463: CAM; Xeno; NbExp=2; IntAct=EBI-2619448, EBI-15916571;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10827969,
CC ECO:0000269|PubMed:24297919, ECO:0000269|PubMed:28029095,
CC ECO:0000269|PubMed:9893979}; Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed in brain (at protein level)
CC (PubMed:10827969). Expressed in cerebellar granule neurons (at protein
CC level) (PubMed:28029095). {ECO:0000269|PubMed:10827969,
CC ECO:0000269|PubMed:28029095}.
CC -!- DOMAIN: The sequence contains 4 internal repeats, each with 5
CC hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged
CC segment (S4). Segments S4 are probably the voltage-sensors and are
CC characterized by a series of positively charged amino acids at every
CC third position. {ECO:0000305}.
CC -!- PTM: May be ubiquitinated by NEDD4L; which would promote its
CC endocytosis.
CC -!- PTM: Phosphorylation at Ser-1506 by PKC in a highly conserved
CC cytoplasmic loop slows inactivation of the sodium channel and reduces
CC peak sodium currents. {ECO:0000269|PubMed:1322892,
CC ECO:0000269|PubMed:1658937, ECO:0000269|PubMed:20131913}.
CC -!- PTM: Sumoylated at Lys-38. Sumoylation is induced by hypoxia, increases
CC voltage-gated sodium current and mediates the early response to acute
CC hypoxia in neurons (PubMed:28029095). Sumoylated SCN2A is located at
CC the cell membrane (PubMed:28029095). {ECO:0000269|PubMed:28029095}.
CC -!- SIMILARITY: Belongs to the sodium channel (TC 1.A.1.10) family.
CC Nav1.2/SCN2A subfamily. {ECO:0000305}.
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DR EMBL; X03639; CAA27287.1; -; mRNA.
DR RefSeq; NP_036779.1; NM_012647.1.
DR PDB; 1BYY; NMR; -; A=1474-1526.
DR PDB; 2KXW; NMR; -; B=1901-1927.
DR PDB; 2M5E; NMR; -; B=1901-1927.
DR PDBsum; 1BYY; -.
DR PDBsum; 2KXW; -.
DR PDBsum; 2M5E; -.
DR AlphaFoldDB; P04775; -.
DR BMRB; P04775; -.
DR SMR; P04775; -.
DR BioGRID; 246890; 6.
DR CORUM; P04775; -.
DR DIP; DIP-57088N; -.
DR IntAct; P04775; 2.
DR STRING; 10116.ENSRNOP00000007069; -.
DR BindingDB; P04775; -.
DR ChEMBL; CHEMBL3399; -.
DR DrugCentral; P04775; -.
DR GuidetoPHARMACOLOGY; 579; -.
DR GlyCosmos; P04775; 10 sites, No reported glycans.
DR GlyGen; P04775; 10 sites.
DR iPTMnet; P04775; -.
DR PhosphoSitePlus; P04775; -.
DR SwissPalm; P04775; -.
DR PaxDb; 10116-ENSRNOP00000007069; -.
DR ABCD; P04775; 1 sequenced antibody.
DR GeneID; 24766; -.
DR KEGG; rno:24766; -.
DR UCSC; RGD:3632; rat.
DR AGR; RGD:3632; -.
DR CTD; 6326; -.
DR RGD; 3632; Scn2a.
DR eggNOG; KOG2301; Eukaryota.
DR InParanoid; P04775; -.
DR OrthoDB; 1110761at2759; -.
DR PhylomeDB; P04775; -.
DR EvolutionaryTrace; P04775; -.
DR PRO; PR:P04775; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0030424; C:axon; IDA:RGD.
DR GO; GO:0043194; C:axon initial segment; IDA:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0014704; C:intercalated disc; ISO:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0033268; C:node of Ranvier; IDA:BHF-UCL.
DR GO; GO:0033270; C:paranode region of axon; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0042734; C:presynaptic membrane; ISO:RGD.
DR GO; GO:0030315; C:T-tubule; ISO:RGD.
DR GO; GO:0001518; C:voltage-gated sodium channel complex; IDA:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; ISO:RGD.
DR GO; GO:0043522; F:leucine zipper domain binding; IPI:RGD.
DR GO; GO:0031402; F:sodium ion binding; IDA:RGD.
DR GO; GO:0099508; F:voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential; IDA:SynGO.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; IDA:UniProtKB.
DR GO; GO:0061564; P:axon development; IEP:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IDA:UniProtKB.
DR GO; GO:0021987; P:cerebral cortex development; IEP:RGD.
DR GO; GO:0022038; P:corpus callosum development; IEP:RGD.
DR GO; GO:0021542; P:dentate gyrus development; ISO:RGD.
DR GO; GO:0008340; P:determination of adult lifespan; ISO:RGD.
DR GO; GO:0008627; P:intrinsic apoptotic signaling pathway in response to osmotic stress; ISS:UniProtKB.
DR GO; GO:0086010; P:membrane depolarization during action potential; IBA:GO_Central.
DR GO; GO:0007613; P:memory; ISS:UniProtKB.
DR GO; GO:0042552; P:myelination; IEP:BHF-UCL.
DR GO; GO:0021675; P:nerve development; ISO:RGD.
DR GO; GO:0007399; P:nervous system development; ISS:UniProtKB.
DR GO; GO:0051402; P:neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0019228; P:neuronal action potential; IDA:UniProtKB.
DR GO; GO:0021554; P:optic nerve development; IEP:RGD.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006814; P:sodium ion transport; IDA:RGD.
DR CDD; cd13433; Na_channel_gate; 1.
DR DisProt; DP02624; -.
DR Gene3D; 1.10.287.70; -; 4.
DR Gene3D; 1.10.238.10; EF-hand; 1.
DR Gene3D; 1.20.5.1190; iswi atpase; 1.
DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 4.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR InterPro; IPR001696; Na_channel_asu.
DR InterPro; IPR044564; Na_chnl_inactivation_gate.
DR InterPro; IPR010526; Na_trans_assoc_dom.
DR InterPro; IPR024583; Na_trans_cytopl.
DR InterPro; IPR043203; VGCC_Ca_Na.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR10037:SF278; SODIUM CHANNEL PROTEIN TYPE 2 SUBUNIT ALPHA; 1.
DR PANTHER; PTHR10037; VOLTAGE-GATED CATION CHANNEL CALCIUM AND SODIUM; 1.
DR Pfam; PF00520; Ion_trans; 4.
DR Pfam; PF06512; Na_trans_assoc; 1.
DR Pfam; PF11933; Na_trans_cytopl; 1.
DR PRINTS; PR00170; NACHANNEL.
DR SMART; SM00015; IQ; 1.
DR SUPFAM; SSF81324; Voltage-gated potassium channels; 4.
DR PROSITE; PS50096; IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; Glycoprotein; Ion channel;
KW Ion transport; Isopeptide bond; Membrane; Phosphoprotein;
KW Reference proteome; Repeat; Sodium; Sodium channel; Sodium transport;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation;
KW Voltage-gated channel.
FT CHAIN 1..2005
FT /note="Sodium channel protein type 2 subunit alpha"
FT /id="PRO_0000048492"
FT TOPO_DOM 1..129
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 130..148
FT /note="Helical; Name=S1 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 149..155
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 156..176
FT /note="Helical; Name=S2 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 177..190
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 191..208
FT /note="Helical; Name=S3 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 209..214
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 215..231
FT /note="Helical; Name=S4 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 232..250
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 251..270
FT /note="Helical; Name=S5 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 271..369
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 370..394
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 395..401
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 402..422
FT /note="Helical; Name=S6 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 423..759
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 760..778
FT /note="Helical; Name=S1 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 779..789
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 790..809
FT /note="Helical; Name=S2 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 810..823
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 824..843
FT /note="Helical; Name=S3 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 844..845
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 846..863
FT /note="Helical; Name=S4 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 864..879
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 880..898
FT /note="Helical; Name=S5 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 899..927
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 928..948
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 949..961
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 962..982
FT /note="Helical; Name=S6 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 983..1209
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1210..1227
FT /note="Helical; Name=S1 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1228..1240
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1241..1259
FT /note="Helical; Name=S2 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1260..1273
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1274..1292
FT /note="Helical; Name=S3 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1293..1300
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1301..1319
FT /note="Helical; Name=S4 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1320..1336
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1337..1356
FT /note="Helical; Name=S5 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1357..1408
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 1409..1430
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1431..1447
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1448..1469
FT /note="Helical; Name=S6 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1470..1532
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1533..1550
FT /note="Helical; Name=S1 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1551..1561
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1562..1580
FT /note="Helical; Name=S2 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1581..1592
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1593..1610
FT /note="Helical; Name=S3 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1611..1623
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1624..1640
FT /note="Helical; Name=S4 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1641..1659
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1660..1677
FT /note="Helical; Name=S5 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1678..1699
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 1700..1722
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1723..1752
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1753..1775
FT /note="Helical; Name=S6 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1776..2005
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REPEAT 111..456
FT /note="I"
FT /evidence="ECO:0000305"
FT REPEAT 741..1013
FT /note="II"
FT /evidence="ECO:0000305"
FT REPEAT 1190..1504
FT /note="III"
FT /evidence="ECO:0000305"
FT REPEAT 1513..1811
FT /note="IV"
FT /evidence="ECO:0000305"
FT DOMAIN 1905..1934
FT /note="IQ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00116"
FT REGION 28..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 494..529
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 591..634
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 917..918
FT /note="Binds SCN2B"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT REGION 1120..1166
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1933..2005
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 28..53
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 510..529
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 591..623
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1933..1959
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1960..1977
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1978..2005
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 330
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 362
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 909
FT /note="Binds SCN2B; via carbonyl oxygen"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 916
FT /note="Binds Mu-conotoxin KIIIA; via amide nitrogen"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 920
FT /note="Binds Mu-conotoxin KIIIA; via carbonyl oxygen"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 945
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 949
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 1374
FT /note="Binds Mu-conotoxin KIIIA; via amide nitrogen"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 1429
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 1443
FT /note="Binds Mu-conotoxin KIIIA"
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT SITE 1489
FT /note="Important for channel closure"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 468
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 471
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 484
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 526
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 528
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 531
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 553
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 554
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:1322892,
FT ECO:0000269|PubMed:20131913, ECO:0007744|PubMed:22673903"
FT MOD_RES 554
FT /note="Phosphoserine; by PKC; in vitro"
FT /evidence="ECO:0000269|PubMed:1322892,
FT ECO:0000269|PubMed:20131913, ECO:0007744|PubMed:22673903"
FT MOD_RES 558
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 573
FT /note="Phosphoserine; by PKC; in vitro"
FT /evidence="ECO:0000269|PubMed:1322892"
FT MOD_RES 576
FT /note="Phosphoserine; by PKC; in vitro"
FT /evidence="ECO:0000269|PubMed:1322892"
FT MOD_RES 589
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 610
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 623
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 687
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 688
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 721
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 1506
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000269|PubMed:1322892,
FT ECO:0000269|PubMed:1658937"
FT MOD_RES 1930
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 1943
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1963
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:16641100"
FT MOD_RES 1966
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT MOD_RES 1971
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:20131913"
FT CARBOHYD 212
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 285
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 291
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 297
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 303
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 308
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 340
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1368
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1382
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 1393
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 278..338
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT DISULFID 910
FT /note="Interchain; with SCN2B or SCN4B"
FT /evidence="ECO:0000269|PubMed:26894959,
FT ECO:0000305|PubMed:24497506"
FT DISULFID 910
FT /note="Interchain; with the conotoxin GVIIJ (when the
FT channel is not linked to SCN2B or SCN4B; the bond to SCN2B
FT or SCN4B protects the channel from the inhibition by
FT toxin)"
FT /evidence="ECO:0000269|PubMed:24497506"
FT DISULFID 912..918
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT DISULFID 950..959
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT DISULFID 1366..1386
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT DISULFID 1731..1746
FT /evidence="ECO:0000250|UniProtKB:Q99250"
FT CROSSLNK 38
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000269|PubMed:28029095"
FT MUTAGEN 38
FT /note="K->Q: Abolishes SUMOylation. No increase of voltage-
FT gated sodium current upon hypoxia."
FT /evidence="ECO:0000269|PubMed:28029095"
FT MUTAGEN 385
FT /note="F->C: Sodium current is irreversibly blocked by
FT methanethiosulfonate (MTSET); the mutated Cys residue has a
FT free thiol susceptible to reaction with MTSET, and
FT inhibition of current is due to the fact that the residue
FT is close to the selectivity filter."
FT /evidence="ECO:0000250|UniProtKB:P15389,
FT ECO:0000269|PubMed:26039939"
FT MUTAGEN 879..881
FT /note="GAL->QQQ: Slowed inactivation and increased
FT persistent current. Gain of function mutation."
FT /evidence="ECO:0000269|PubMed:11166117"
FT MUTAGEN 910
FT /note="C->L: >1000-fold reduction of sensitivity to the
FT conotoxin GVIIJ(SSG)."
FT /evidence="ECO:0000269|PubMed:24497506"
FT MUTAGEN 1489
FT /note="F->Q: Strongly impairs channel inactivation."
FT /evidence="ECO:0000269|PubMed:9893979"
FT MUTAGEN 1506
FT /note="S->A: Blocks the reduction of Na+ current and the
FT slowing of inactivation caused by PKC."
FT /evidence="ECO:0000269|PubMed:1658937"
FT MUTAGEN 1613
FT /note="E->D: Increase in sensitivity to the scorpion toxin
FT BMK M1."
FT /evidence="ECO:0000269|PubMed:20678086"
FT MUTAGEN 1975
FT /note="Y->A: Abolishes interaction with NEDD4L."
FT /evidence="ECO:0000269|PubMed:15548568"
FT HELIX 1492..1502
FT /evidence="ECO:0007829|PDB:1BYY"
FT HELIX 1904..1922
FT /evidence="ECO:0007829|PDB:2KXW"
SQ SEQUENCE 2005 AA; 227874 MW; 861BE583D79F8324 CRC64;
MARSVLVPPG PDSFRFFTRE SLAAIEQRIA EEKAKRPKQE RKDEDDENGP KPNSDLEAGK
SLPFIYGDIP PEMVSEPLED LDPYYINKKT FIVLNKGKAI SRFSATSALY ILTPFNPIRK
LAIKILVHSL FNVLIMCTIL TNCVFMTMSN PPDWTKNVEY TFTGIYTFES LIKILARGFC
LEDFTFLRNP WNWLDFTVIT FAYVTEFVNL GNVSALRTFR VLRALKTISV IPGLKTIVGA
LIQSVKKLSD VMILTVFCLS VFALIGLQLF MGNLRNKCLQ WPPDNSTFEI NITSFFNNSL
DWNGTAFNRT VNMFNWDEYI EDKSHFYFLE GQNDALLCGN SSDAGQCPEG YICVKAGRNP
NYGYTSFDTF SWAFLSLFRL MTQDFWENLY QLTLRAAGKT YMIFFVLVIF LGSFYLINLI
LAVVAMAYEE QNQATLEEAE QKEAEFQQML EQLKKQQEEA QAAAAAASAE SRDFSGAGGI
GVFSESSSVA SKLSSKSEKE LKNRRKKKKQ KEQAGEEEKE DAVRKSASED SIRKKGFQFS
LEGSRLTYEK RFSSPHQSLL SIRGSLFSPR RNSRASLFNF KGRVKDIGSE NDFADDEHST
FEDNDSRRDS LFVPHRHGER RPSNVSQASR ASRGIPTLPM NGKMHSAVDC NGVVSLVGGP
SALTSPVGQL LPEGTTTETE IRKRRSSSYH VSMDLLEDPS RQRAMSMASI LTNTMEELEE
SRQKCPPCWY KFANMCLIWD CCKPWLKVKH VVNLVVMDPF VDLAITICIV LNTLFMAMEH
YPMTEQFSSV LSVGNLVFTG IFTAEMFLKI IAMDPYYYFQ EGWNIFDGFI VSLSLMELGL
ANVEGLSVLR SFRLLRVFKL AKSWPTLNML IKIIGNSVGA LGNLTLVLAI IVFIFAVVGM
QLFGKSYKEC VCKISNDCEL PRWHMHHFFH SFLIVFRVLC GEWIETMWDC MEVAGQTMCL
TVFMMVMVIG NLVVLNLFLA LLLSSFSSDN LAATDDDNEM NNLQIAVGRM QKGIDFVKRK
IREFIQKAFV RKQKALDEIK PLEDLNNKKD SCISNHTTIE IGKDLNYLKD GNGTTSGIGS
SVEKYVVDES DYMSFINNPS LTVTVPIALG ESDFENLNTE EFSSESDMEE SKEKLNATSS
SEGSTVDIGA PAEGEQPEAE PEESLEPEAC FTEDCVRKFK CCQISIEEGK GKLWWNLRKT
CYKIVEHNWF ETFIVFMILL SSGALAFEDI YIEQRKTIKT MLEYADKVFT YIFILEMLLK
WVAYGFQMYF TNAWCWLDFL IVDVSLVSLT ANALGYSELG AIKSLRTLRA LRPLRALSRF
EGMRVVVNAL LGAIPSIMNV LLVCLIFWLI FSIMGVNLFA GKFYHCINYT TGEMFDVSVV
NNYSECQALI ESNQTARWKN VKVNFDNVGL GYLSLLQVAT FKGWMDIMYA AVDSRNVELQ
PKYEDNLYMY LYFVIFIIFG SFFTLNLFIG VIIDNFNQQK KKFGGQDIFM TEEQKKYYNA
MKKLGSKKPQ KPIPRPANKF QGMVFDFVTK QVFDISIMIL ICLNMVTMMV ETDDQSQEMT
NILYWINLVF IVLFTGECVL KLISLRHYYF TIGWNIFDFV VVILSIVGMF LAELIEKYFV
SPTLFRVIRL ARIGRILRLI KGAKGIRTLL FALMMSLPAL FNIGLLLFLV MFIYAIFGMS
NFAYVKREVG IDDMFNFETF GNSMICLFQI TTSAGWDGLL APILNSGPPD CDPEKDHPGS
SVKGDCGNPS VGIFFFVSYI IISFLVVVNM YIAVILENFS VATEESAEPL SEDDFEMFYE
VWEKFDPDAT QFIEFCKLSD FAAALDPPLL IAKPNKVQLI AMDLPMVSGD RIHCLDILFA
FTKRVLGESG EMDALRIQME ERFMASNPSK VSYEPITTTL KRKQEEVSAI VIQRAYRRYL
LKQKVKKVSS IYKKDKGKED EGTPIKEDII TDKLNENSTP EKTDVTPSTT SPPSYDSVTK
PEKEKFEKDK SEKEDKGKDI RESKK
//
