TMC8_HUMAN
ID TMC8_HUMAN Reviewed; 726 AA.
AC Q8IU68; Q2YDC0; Q8IWU7; Q8N358; Q8NF04;
DT 06-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Transmembrane channel-like protein 8;
DE AltName: Full=Epidermodysplasia verruciformis protein 2;
GN Name=TMC8; Synonyms=EVER2, EVIN2;
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] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION,
RP INVOLVEMENT IN EV2, AND VARIANT EV2 362-GLU--LEU-726 DEL.
RX PubMed=12426567; DOI=10.1038/ng1044;
RA Ramoz N., Rueda L.-A., Bouadjar B., Montoya L.-S., Orth G., Favre M.;
RT "Mutations in two adjacent novel genes are associated with
RT epidermodysplasia verruciformis.";
RL Nat. Genet. 32:579-581(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=12906855; DOI=10.1016/s0888-7543(03)00154-x;
RA Kurima K., Yang Y., Sorber K., Griffith A.J.;
RT "Characterization of the transmembrane channel-like (TMC) gene family:
RT functional clues from hearing loss and epidermodysplasia verruciformis.";
RL Genomics 82:300-308(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ILE-306.
RC TISSUE=Spleen;
RA Jikuya H., Takano J., Kikuno R., Nagase T., Ohara O.;
RT "The nucleotide sequence of a long cDNA clone isolated from human spleen.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Blood;
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 [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-658, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [8]
RP INVOLVEMENT IN EV2, AND VARIANT ILE-306.
RX PubMed=28646613; DOI=10.1111/jdv.14431;
RA Imahorn E., Yueksel Z., Spoerri I., Guerel G., Imhof C., Saracoglu Z.N.,
RA Koku Aksu A.E., Rady P.L., Tyring S.K., Kempf W., Itin P.H., Burger B.;
RT "Novel TMC8 splice site mutation in epidermodysplasia verruciformis and
RT review of HPV infections in patients with the disease.";
RL J. Eur. Acad. Dermatol. Venereol. 31:1722-1726(2017).
RN [9]
RP INTERACTION WITH CIB1.
RX PubMed=30068544; DOI=10.1084/jem.20170308;
RA de Jong S.J., Crequer A., Matos I., Hum D., Gunasekharan V., Lorenzo L.,
RA Jabot-Hanin F., Imahorn E., Arias A.A., Vahidnezhad H., Youssefian L.,
RA Markle J.G., Patin E., D'Amico A., Wang C.Q.F., Full F., Ensser A.,
RA Leisner T.M., Parise L.V., Bouaziz M., Maya N.P., Cadena X.R., Saka B.,
RA Saeidian A.H., Aghazadeh N., Zeinali S., Itin P., Krueger J.G., Laimins L.,
RA Abel L., Fuchs E., Uitto J., Franco J.L., Burger B., Orth G., Jouanguy E.,
RA Casanova J.L.;
RT "The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity
RT to beta-papillomaviruses.";
RL J. Exp. Med. 215:2289-2310(2018).
CC -!- FUNCTION: Probable ion channel. {ECO:0000250}.
CC -!- SUBUNIT: Interacts with CIB1. {ECO:0000269|PubMed:30068544}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:12426567}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:12426567}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Large EVER2;
CC IsoId=Q8IU68-1; Sequence=Displayed;
CC Name=2; Synonyms=Small EVER2;
CC IsoId=Q8IU68-2; Sequence=VSP_016448;
CC -!- TISSUE SPECIFICITY: Expressed in placenta, prostate and testis.
CC {ECO:0000269|PubMed:12906855}.
CC -!- DISEASE: Epidermodysplasia verruciformis 2 (EV2) [MIM:618231]: A form
CC of epidermodysplasia verruciformis, a rare genodermatosis associated
CC with a high risk of skin carcinoma that results from an abnormal
CC susceptibility to infection by specific human papillomaviruses,
CC including the oncogenic HPV5. Infection leads to the early development
CC of disseminated flat wart-like and pityriasis versicolor-like skin
CC lesions. Cutaneous Bowen's carcinomas in situ and invasive squamous
CC cell carcinomas develop in about half of the patients, mainly on sun-
CC exposed skin areas. EV2 inheritance is autosomal recessive.
CC {ECO:0000269|PubMed:12426567, ECO:0000269|PubMed:28646613}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the TMC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC03459.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BC028076; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=TMC8base; Note=TMC8 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/TMC8base/";
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DR EMBL; AY057380; AAL25837.1; -; mRNA.
DR EMBL; AY099358; AAM44454.1; -; mRNA.
DR EMBL; AY099359; AAM44455.1; -; mRNA.
DR EMBL; AY236500; AAP69878.1; -; mRNA.
DR EMBL; AK090478; BAC03459.1; ALT_INIT; mRNA.
DR EMBL; AC021593; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028076; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC110296; AAI10297.1; -; mRNA.
DR CCDS; CCDS32749.1; -. [Q8IU68-1]
DR RefSeq; NP_689681.2; NM_152468.4. [Q8IU68-1]
DR AlphaFoldDB; Q8IU68; -.
DR SMR; Q8IU68; -.
DR BioGRID; 127037; 6.
DR IntAct; Q8IU68; 1.
DR STRING; 9606.ENSP00000325561; -.
DR TCDB; 1.A.17.4.11; the calcium-dependent chloride channel (ca-clc) family.
DR GlyGen; Q8IU68; 2 sites.
DR iPTMnet; Q8IU68; -.
DR PhosphoSitePlus; Q8IU68; -.
DR SwissPalm; Q8IU68; -.
DR BioMuta; TMC8; -.
DR DMDM; 74714272; -.
DR jPOST; Q8IU68; -.
DR MassIVE; Q8IU68; -.
DR PaxDb; Q8IU68; -.
DR PeptideAtlas; Q8IU68; -.
DR PRIDE; Q8IU68; -.
DR ProteomicsDB; 70513; -. [Q8IU68-1]
DR ProteomicsDB; 70514; -. [Q8IU68-2]
DR Antibodypedia; 32534; 198 antibodies from 28 providers.
DR DNASU; 147138; -.
DR Ensembl; ENST00000318430.10; ENSP00000325561.4; ENSG00000167895.15. [Q8IU68-1]
DR Ensembl; ENST00000589691.1; ENSP00000467482.1; ENSG00000167895.15. [Q8IU68-2]
DR GeneID; 147138; -.
DR KEGG; hsa:147138; -.
DR MANE-Select; ENST00000318430.10; ENSP00000325561.4; NM_152468.5; NP_689681.2.
DR UCSC; uc002jup.3; human. [Q8IU68-1]
DR CTD; 147138; -.
DR DisGeNET; 147138; -.
DR GeneCards; TMC8; -.
DR HGNC; HGNC:20474; TMC8.
DR HPA; ENSG00000167895; Group enriched (bone marrow, intestine, lymphoid tissue).
DR MalaCards; TMC8; -.
DR MIM; 605829; gene.
DR MIM; 618231; phenotype.
DR neXtProt; NX_Q8IU68; -.
DR OpenTargets; ENSG00000167895; -.
DR Orphanet; 302; Epidermodysplasia verruciformis.
DR PharmGKB; PA134892288; -.
DR VEuPathDB; HostDB:ENSG00000167895; -.
DR eggNOG; ENOG502RKT7; Eukaryota.
DR GeneTree; ENSGT01050000244894; -.
DR HOGENOM; CLU_013958_3_1_1; -.
DR InParanoid; Q8IU68; -.
DR OMA; TNTYLFY; -.
DR OrthoDB; 1048914at2759; -.
DR PhylomeDB; Q8IU68; -.
DR TreeFam; TF313462; -.
DR PathwayCommons; Q8IU68; -.
DR SignaLink; Q8IU68; -.
DR BioGRID-ORCS; 147138; 13 hits in 1074 CRISPR screens.
DR ChiTaRS; TMC8; human.
DR GeneWiki; TMC8; -.
DR GenomeRNAi; 147138; -.
DR Pharos; Q8IU68; Tbio.
DR PRO; PR:Q8IU68; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q8IU68; protein.
DR Bgee; ENSG00000167895; Expressed in granulocyte and 147 other tissues.
DR ExpressionAtlas; Q8IU68; baseline and differential.
DR Genevisible; Q8IU68; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:InterPro.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0008381; F:mechanosensitive ion channel activity; IBA:GO_Central.
DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB.
DR GO; GO:0043120; F:tumor necrosis factor binding; IPI:UniProtKB.
DR GO; GO:0032091; P:negative regulation of protein binding; IDA:UniProtKB.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IDA:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; IDA:UniProtKB.
DR GO; GO:1902041; P:regulation of extrinsic apoptotic signaling pathway via death domain receptors; IDA:UniProtKB.
DR GO; GO:0055069; P:zinc ion homeostasis; IDA:UniProtKB.
DR InterPro; IPR038900; TMC.
DR InterPro; IPR012496; TMC_dom.
DR PANTHER; PTHR23302; PTHR23302; 1.
DR Pfam; PF07810; TMC; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Disease variant; Endoplasmic reticulum; Glycoprotein;
KW Ion channel; Ion transport; Membrane; Phosphoprotein; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..726
FT /note="Transmembrane channel-like protein 8"
FT /id="PRO_0000185386"
FT TOPO_DOM 1..114
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 115..135
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 136..200
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 201..221
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 222..299
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 300..320
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 321..338
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 339..359
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 360..426
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 427..447
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 448..488
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 489..509
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 510..531
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 532..552
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 553..594
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 595..615
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 616..726
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 651..726
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TN58"
FT MOD_RES 658
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 673
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7TN58"
FT CARBOHYD 148
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 567
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..223
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12426567"
FT /id="VSP_016448"
FT VARIANT 306
FT /note="N -> I (in dbSNP:rs7208422)"
FT /evidence="ECO:0000269|PubMed:28646613, ECO:0000269|Ref.3"
FT /id="VAR_023964"
FT VARIANT 362..726
FT /note="Missing (in EV2)"
FT /evidence="ECO:0000269|PubMed:12426567"
FT /id="VAR_081777"
FT VARIANT 501
FT /note="V -> I (in dbSNP:rs11651675)"
FT /id="VAR_052337"
FT CONFLICT 5
FT /note="R -> W (in Ref. 3; BAC03459)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 726 AA; 81641 MW; AA3F4A01A6C315EF CRC64;
MLLPRSVSSE RAPGVPEPEE LWEAEMERLR GSGTPVRGLP YAMMDKRLIW QLREPAGVQT
LRWQRWQRRR QTVERRLREA AQRLARGLGL WEGALYEIGG LFGTGIRSYF TFLRFLLLLN
LLSLLLTASF VLLPLVWLRP PDPGPTLNLT LQCPGSRQSP PGVLRFHNQL WHVLTGRAFT
NTYLFYGAYR VGPESSSVYS IRLAYLLSPL ACLLLCFCGT LRRMVKGLPQ KTLLGQGYQA
PLSAKVFSSW DFCIRVQEAA TIKKHEISNE FKVELEEGRR FQLMQQQTRA QTACRLLSYL
RVNVLNGLLV VGAISAIFWA TKYSQDNKEE SLFLLLQYLP PGVIALVNFL GPLLFTFLVQ
LENYPPNTEV NLTLIWCVVL KLASLGMFSV SLGQTILCIG RDKSSCESYG YNVCDYQCWE
NSVGEELYKL SIFNFLLTVA FAFLVTLPRR LLVDRFSGRF WAWLEREEFL VPKNVLDIVA
GQTVTWMGLF YCPLLPLLNS VFLFLTFYIK KYTLLKNSRA SSRPFRASSS TFFFQLVLLL
GLLLAAVPLG YVVSSIHSSW DCGLFTNYSA PWQVVPELVA LGLPPIGQRA LHYLGSHAFS
FPLLIMLSLV LTVCVSQTQA NARAIHRLRK QLVWQVQEKW HLVEDLSRLL PEPGPSDSPG
PKYPASQASR PQSFCPGCPC PGSPGHQAPR PGPSVVDAAG LRSPCPGQHG APASARRFRF
PSGAEL
