SCN4B_HUMAN
ID SCN4B_HUMAN Reviewed; 228 AA.
AC Q8IWT1; E9PPT5; Q6PIG5;
DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Sodium channel subunit beta-4;
DE Flags: Precursor;
GN Name=SCN4B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=12930796; DOI=10.1523/jneurosci.23-20-07577.2003;
RA Yu F.H., Westenbroek R.E., Silos-Santiago I., McCormick K.A., Lawson D.,
RA Ge P., Ferriera H., Lilly J., DiStefano P.S., Catterall W.A., Scheuer T.,
RA Curtis R.;
RT "Sodium channel beta4, a new disulfide-linked auxiliary subunit with
RT similarity to beta2.";
RL J. Neurosci. 23:7577-7585(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [3]
RP PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.72 ANGSTROMS) OF 32-157, FUNCTION, SUBCELLULAR
RP LOCATION, SUBUNIT, DISULFIDE BOND, GLYCOSYLATION, INTERACTION WITH SCN2A,
RP AND MUTAGENESIS OF CYS-58 AND CYS-131.
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 [5]
RP VARIANT LQT10 PHE-179, AND CHARACTERIZATION OF VARIANT LQT10 PHE-179.
RX PubMed=17592081; DOI=10.1161/circulationaha.106.659086;
RA Medeiros-Domingo A., Kaku T., Tester D.J., Iturralde-Torres P., Itty A.,
RA Ye B., Valdivia C., Ueda K., Canizales-Quinteros S., Tusie-Luna M.T.,
RA Makielski J.C., Ackerman M.J.;
RT "SCN4B-encoded sodium channel beta4 subunit in congenital long-QT
RT syndrome.";
RL Circulation 116:134-142(2007).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=21051419; DOI=10.1093/cvr/cvq348;
RA Olesen M.S., Jespersen T., Nielsen J.B., Liang B., Moller D.V., Hedley P.,
RA Christiansen M., Varro A., Olesen S.P., Haunso S., Schmitt N.,
RA Svendsen J.H.;
RT "Mutations in sodium channel beta-subunit SCN3B are associated with early-
RT onset lone atrial fibrillation.";
RL Cardiovasc. Res. 89:786-793(2011).
RN [7]
RP INVOLVEMENT IN ATFB17, AND VARIANTS ATFB17 GLY-162 AND LEU-166.
RX PubMed=23604097; DOI=10.3892/ijmm.2013.1355;
RA Li R.G., Wang Q., Xu Y.J., Zhang M., Qu X.K., Liu X., Fang W.Y., Yang Y.Q.;
RT "Mutations of the SCN4B-encoded sodium channel beta4 subunit in familial
RT atrial fibrillation.";
RL Int. J. Mol. Med. 32:144-150(2013).
CC -!- FUNCTION: Modulates channel gating kinetics. Causes negative shifts in
CC the voltage dependence of activation of certain alpha sodium channels,
CC but does not affect the voltage dependence of inactivation. Modulates
CC the susceptibility of the sodium channel to inhibition by toxic
CC peptides from spider, scorpion, wasp and sea anemone venom.
CC {ECO:0000269|PubMed:24297919}.
CC -!- SUBUNIT: The voltage-sensitive sodium channel consists of an ion
CC conducting pore forming alpha-subunit (SCN2A) regulated by one or more
CC beta subunits (SCN1B, SCN2B, SCN3B and SCN4B). SCN1B and SCN3B are non-
CC covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked
CC to SCN2A (PubMed:24297919). {ECO:0000269|PubMed:24297919}.
CC -!- INTERACTION:
CC Q8IWT1; O95070: YIF1A; NbExp=3; IntAct=EBI-23705473, EBI-2799703;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24297919};
CC Single-pass type I membrane protein {ECO:0000269|PubMed:24297919}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8IWT1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IWT1-2; Sequence=VSP_053913;
CC Name=3;
CC IsoId=Q8IWT1-3; Sequence=VSP_046971;
CC -!- TISSUE SPECIFICITY: Expressed at a high level in dorsal root ganglia,
CC at a lower level in brain, spinal cord, skeletal muscle and heart.
CC Expressed in the atrium. {ECO:0000269|PubMed:12930796,
CC ECO:0000269|PubMed:21051419}.
CC -!- PTM: Contains an interchain disulfide bond with SCN2A.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:24297919}.
CC -!- DISEASE: Long QT syndrome 10 (LQT10) [MIM:611819]: A heart disorder
CC characterized by a prolonged QT interval on the ECG and polymorphic
CC ventricular arrhythmias. They cause syncope and sudden death in
CC response to exercise or emotional stress, and can present with a
CC sentinel event of sudden cardiac death in infancy.
CC {ECO:0000269|PubMed:17592081}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Atrial fibrillation, familial, 17 (ATFB17) [MIM:611819]: A
CC familial form of atrial fibrillation, a common sustained cardiac rhythm
CC disturbance. Atrial fibrillation is characterized by disorganized
CC atrial electrical activity and ineffective atrial contraction promoting
CC blood stasis in the atria and reduces ventricular filling. It can
CC result in palpitations, syncope, thromboembolic stroke, and congestive
CC heart failure. {ECO:0000269|PubMed:23604097}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the sodium channel auxiliary subunit SCN4B (TC
CC 8.A.17) family. {ECO:0000305}.
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DR EMBL; AY149967; AAN74584.1; -; mRNA.
DR EMBL; AP002800; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035017; AAH35017.1; -; mRNA.
DR CCDS; CCDS44744.1; -. [Q8IWT1-3]
DR CCDS; CCDS8389.1; -. [Q8IWT1-1]
DR RefSeq; NP_001135820.1; NM_001142348.1. [Q8IWT1-3]
DR RefSeq; NP_001135821.1; NM_001142349.1. [Q8IWT1-2]
DR RefSeq; NP_777594.1; NM_174934.3. [Q8IWT1-1]
DR PDB; 4MZ2; X-ray; 1.72 A; A=32-157.
DR PDB; 4MZ3; X-ray; 1.74 A; A/B=32-157.
DR PDB; 5XAW; X-ray; 2.10 A; A/B=30-152.
DR PDB; 6VSV; X-ray; 1.62 A; A=32-157.
DR PDB; 7DTD; EM; 3.30 A; B=1-228.
DR PDBsum; 4MZ2; -.
DR PDBsum; 4MZ3; -.
DR PDBsum; 5XAW; -.
DR PDBsum; 6VSV; -.
DR PDBsum; 7DTD; -.
DR AlphaFoldDB; Q8IWT1; -.
DR SMR; Q8IWT1; -.
DR BioGRID; 112235; 5.
DR IntAct; Q8IWT1; 1.
DR STRING; 9606.ENSP00000322460; -.
DR DrugBank; DB05541; Brivaracetam.
DR DrugBank; DB00907; Cocaine.
DR DrugBank; DB13269; Dichlorobenzyl alcohol.
DR DrugBank; DB13961; Fish oil.
DR DrugBank; DB00776; Oxcarbazepine.
DR DrugBank; DB00243; Ranolazine.
DR DrugBank; DB00313; Valproic acid.
DR DrugBank; DB00909; Zonisamide.
DR DrugCentral; Q8IWT1; -.
DR TCDB; 8.A.17.2.2; the na(+) channel auxiliary subunit Beta1-Beta4 (sca-Beta) family.
DR GlyGen; Q8IWT1; 3 sites.
DR iPTMnet; Q8IWT1; -.
DR PhosphoSitePlus; Q8IWT1; -.
DR BioMuta; SCN4B; -.
DR DMDM; 57012701; -.
DR jPOST; Q8IWT1; -.
DR MassIVE; Q8IWT1; -.
DR PaxDb; Q8IWT1; -.
DR PeptideAtlas; Q8IWT1; -.
DR PRIDE; Q8IWT1; -.
DR ProteomicsDB; 22813; -.
DR ProteomicsDB; 70889; -. [Q8IWT1-1]
DR ProteomicsDB; 70890; -. [Q8IWT1-2]
DR Antibodypedia; 2645; 144 antibodies from 27 providers.
DR DNASU; 6330; -.
DR Ensembl; ENST00000324727.9; ENSP00000322460.4; ENSG00000177098.9. [Q8IWT1-1]
DR Ensembl; ENST00000529878.1; ENSP00000436343.1; ENSG00000177098.9. [Q8IWT1-3]
DR GeneID; 6330; -.
DR KEGG; hsa:6330; -.
DR MANE-Select; ENST00000324727.9; ENSP00000322460.4; NM_174934.4; NP_777594.1.
DR UCSC; uc001pse.4; human. [Q8IWT1-1]
DR CTD; 6330; -.
DR DisGeNET; 6330; -.
DR GeneCards; SCN4B; -.
DR GeneReviews; SCN4B; -.
DR HGNC; HGNC:10592; SCN4B.
DR HPA; ENSG00000177098; Tissue enhanced (brain, tongue).
DR MalaCards; SCN4B; -.
DR MIM; 608256; gene.
DR MIM; 611819; phenotype.
DR neXtProt; NX_Q8IWT1; -.
DR OpenTargets; ENSG00000177098; -.
DR Orphanet; 334; Familial atrial fibrillation.
DR Orphanet; 101016; Romano-Ward syndrome.
DR PharmGKB; PA35007; -.
DR VEuPathDB; HostDB:ENSG00000177098; -.
DR eggNOG; ENOG502QTZ6; Eukaryota.
DR GeneTree; ENSGT01030000234556; -.
DR HOGENOM; CLU_104235_0_0_1; -.
DR InParanoid; Q8IWT1; -.
DR OMA; EGQYICF; -.
DR PhylomeDB; Q8IWT1; -.
DR TreeFam; TF331728; -.
DR PathwayCommons; Q8IWT1; -.
DR Reactome; R-HSA-445095; Interaction between L1 and Ankyrins.
DR Reactome; R-HSA-5576892; Phase 0 - rapid depolarisation.
DR Reactome; R-HSA-9717207; Sensory perception of sweet, bitter, and umami (glutamate) taste.
DR SignaLink; Q8IWT1; -.
DR BioGRID-ORCS; 6330; 8 hits in 1068 CRISPR screens.
DR ChiTaRS; SCN4B; human.
DR GeneWiki; SCN4B; -.
DR GenomeRNAi; 6330; -.
DR Pharos; Q8IWT1; Tbio.
DR PRO; PR:Q8IWT1; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q8IWT1; protein.
DR Bgee; ENSG00000177098; Expressed in lateral globus pallidus and 158 other tissues.
DR ExpressionAtlas; Q8IWT1; baseline and differential.
DR Genevisible; Q8IWT1; HS.
DR GO; GO:0014704; C:intercalated disc; ISS:BHF-UCL.
DR GO; GO:0031226; C:intrinsic component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0001518; C:voltage-gated sodium channel complex; IDA:UniProtKB.
DR GO; GO:0017080; F:sodium channel regulator activity; IDA:UniProtKB.
DR GO; GO:0044325; F:transmembrane transporter binding; IPI:BHF-UCL.
DR GO; GO:0005244; F:voltage-gated ion channel activity; IEA:UniProtKB-KW.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; IDA:UniProtKB.
DR GO; GO:0086006; F:voltage-gated sodium channel activity involved in cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0086016; P:AV node cell action potential; IMP:BHF-UCL.
DR GO; GO:0086002; P:cardiac muscle cell action potential involved in contraction; IMP:BHF-UCL.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0086012; P:membrane depolarization during cardiac muscle cell action potential; IMP:BHF-UCL.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IDA:BHF-UCL.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:2000649; P:regulation of sodium ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0060307; P:regulation of ventricular cardiac muscle cell membrane repolarization; IMP:BHF-UCL.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:0006814; P:sodium ion transport; IDA:UniProtKB.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR013106; Ig_V-set.
DR InterPro; IPR000920; Myelin_P0-rel.
DR InterPro; IPR044572; Na_channel_b4.
DR PANTHER; PTHR13869; PTHR13869; 1.
DR PANTHER; PTHR13869:SF14; PTHR13869:SF14; 1.
DR Pfam; PF07686; V-set; 1.
DR SMART; SM00409; IG; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Atrial fibrillation; Cell membrane;
KW Disease variant; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Ion channel; Ion transport; Long QT syndrome; Membrane; Reference proteome;
KW Signal; Sodium; Sodium channel; Sodium transport; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT CHAIN 31..228
FT /note="Sodium channel subunit beta-4"
FT /id="PRO_0000014937"
FT TOPO_DOM 31..162
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 163..183
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 184..228
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 31..148
FT /note="Ig-like C2-type"
FT REGION 200..228
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 45
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 113
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 53..131
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:24297919"
FT DISULFID 58
FT /note="Interchain; with alpha subunit"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:24297919"
FT VAR_SEQ 1..110
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_053913"
FT VAR_SEQ 21..155
FT /note="GLFLLPVTLSLEVSVGKATDIYAVNGTEILLPCTFSSCFGFEDLHFRWTYNS
FT SDAFKILIEGTVKNEKSDPKVTLKDDDRITLVGSTKEKMNNISIVLRDLEFSDTGKYTC
FT HVKNPKENNLQHHATIFLQVVDRL -> V (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_046971"
FT VARIANT 162
FT /note="V -> G (in ATFB17; dbSNP:rs587777559)"
FT /evidence="ECO:0000269|PubMed:23604097"
FT /id="VAR_071317"
FT VARIANT 166
FT /note="I -> L (in ATFB17; dbSNP:rs587777560)"
FT /evidence="ECO:0000269|PubMed:23604097"
FT /id="VAR_071318"
FT VARIANT 179
FT /note="L -> F (in LQT10; increase in late sodium current;
FT dbSNP:rs121434386)"
FT /evidence="ECO:0000269|PubMed:17592081"
FT /id="VAR_043488"
FT MUTAGEN 58
FT /note="C->A: Abolishes regulation of channel activity."
FT /evidence="ECO:0000269|PubMed:24297919"
FT MUTAGEN 131
FT /note="C->A,W: Decreases protein stability. Causes
FT conformation changes that impair interaction with the alpha
FT subunit."
FT /evidence="ECO:0000269|PubMed:24297919"
FT CONFLICT 40
FT /note="D -> Y (in Ref. 3; AAH35017)"
FT /evidence="ECO:0000305"
FT STRAND 32..34
FT /evidence="ECO:0007829|PDB:5XAW"
FT STRAND 39..44
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 49..51
FT /evidence="ECO:0007829|PDB:6VSV"
FT TURN 58..60
FT /evidence="ECO:0007829|PDB:4MZ3"
FT STRAND 62..71
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 76..86
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 92..96
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 101..103
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 116..118
FT /evidence="ECO:0007829|PDB:6VSV"
FT HELIX 123..125
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 127..135
FT /evidence="ECO:0007829|PDB:6VSV"
FT HELIX 136..138
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 140..143
FT /evidence="ECO:0007829|PDB:6VSV"
FT STRAND 147..152
FT /evidence="ECO:0007829|PDB:6VSV"
SQ SEQUENCE 228 AA; 24969 MW; 2F17E1210E8EFEF8 CRC64;
MPGAGDGGKA PARWLGTGLL GLFLLPVTLS LEVSVGKATD IYAVNGTEIL LPCTFSSCFG
FEDLHFRWTY NSSDAFKILI EGTVKNEKSD PKVTLKDDDR ITLVGSTKEK MNNISIVLRD
LEFSDTGKYT CHVKNPKENN LQHHATIFLQ VVDRLEEVDN TVTLIILAVV GGVIGLLILI
LLIKKLIIFI LKKTREKKKE CLVSSSGNDN TENGLPGSKA EEKPPSKV
