TRPA1_HUMAN
ID TRPA1_HUMAN Reviewed; 1119 AA.
AC O75762; A6NIN6;
DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Transient receptor potential cation channel subfamily A member 1 {ECO:0000312|HGNC:HGNC:497};
DE AltName: Full=Ankyrin-like with transmembrane domains protein 1 {ECO:0000312|HGNC:HGNC:497};
DE AltName: Full=Transformation-sensitive protein p120 {ECO:0000303|PubMed:10066796};
DE Short=p120 {ECO:0000303|PubMed:10066796};
DE AltName: Full=Wasabi receptor {ECO:0000303|PubMed:25855297, ECO:0000303|PubMed:31447178};
GN Name=TRPA1 {ECO:0000312|HGNC:HGNC:497};
GN Synonyms=ANKTM1 {ECO:0000312|HGNC:HGNC:497};
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], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
RP VARIANTS CYS-3; THR-58 AND ASN-186.
RC TISSUE=Lung;
RX PubMed=10066796; DOI=10.1074/jbc.274.11.7325;
RA Jaquemar D., Schenker T., Trueb B.;
RT "An ankyrin-like protein with transmembrane domains is specifically lost
RT after oncogenic transformation of human fibroblasts.";
RL J. Biol. Chem. 274:7325-7333(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-621; CYS-641; CYS-665 AND
RP LYS-710.
RX PubMed=17164327; DOI=10.1073/pnas.0609598103;
RA Hinman A., Chuang H.H., Bautista D.M., Julius D.;
RT "TRP channel activation by reversible covalent modification.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:19564-19568(2006).
RN [4]
RP ACTIVITY REGULATION.
RX PubMed=17567811; DOI=10.1523/jneurosci.0623-07.2007;
RA Kim D., Cavanaugh E.J.;
RT "Requirement of a soluble intracellular factor for activation of transient
RT receptor potential A1 by pungent chemicals: role of inorganic
RT polyphosphates.";
RL J. Neurosci. 27:6500-6509(2007).
RN [5]
RP FUNCTION, ACTIVITY REGULATION, HYDROXYLATION AT PRO-394, OXIDATION AT
RP CYS-633 AND CYS-856, MUTAGENESIS OF CYS-173; CYS-192; PRO-394; CYS-621;
RP CYS-633; CYS-641; CYS-665 AND CYS-856, AND SUBCELLULAR LOCATION.
RX PubMed=21873995; DOI=10.1038/nchembio.640;
RA Takahashi N., Kuwaki T., Kiyonaka S., Numata T., Kozai D., Mizuno Y.,
RA Yamamoto S., Naito S., Knevels E., Carmeliet P., Oga T., Kaneko S.,
RA Suga S., Nokami T., Yoshida J., Mori Y.;
RT "TRPA1 underlies a sensing mechanism for O2.";
RL Nat. Chem. Biol. 7:701-711(2011).
RN [6]
RP ACTIVITY REGULATION.
RX PubMed=21402443; DOI=10.1016/j.pain.2011.01.049;
RA Chen J., Joshi S.K., DiDomenico S., Perner R.J., Mikusa J.P., Gauvin D.M.,
RA Segreti J.A., Han P., Zhang X.F., Niforatos W., Bianchi B.R., Baker S.J.,
RA Zhong C., Simler G.H., McDonald H.A., Schmidt R.G., McGaraughty S.P.,
RA Chu K.L., Faltynek C.R., Kort M.E., Reilly R.M., Kym P.R.;
RT "Selective blockade of TRPA1 channel attenuates pathological pain without
RT altering noxious cold sensation or body temperature regulation.";
RL Pain 152:1165-1172(2011).
RN [7]
RP FUNCTION.
RX PubMed=23199233; DOI=10.1186/1745-9974-8-11;
RA Buday T., Brozmanova M., Biringerova Z., Gavliakova S., Poliacek I.,
RA Calkovsky V., Shetthalli M.V., Plevkova J.;
RT "Modulation of cough response by sensory inputs from the nose - role of
RT trigeminal TRPA1 versus TRPM8 channels.";
RL Cough 8:11-11(2012).
RN [8]
RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND ACTIVATION BY ELECTROPHILES.
RX PubMed=25389312; DOI=10.1073/pnas.1412689111;
RA Moparthi L., Survery S., Kreir M., Simonsen C., Kjellbom P.,
RA Hoegestaett E.D., Johanson U., Zygmunt P.M.;
RT "Human TRPA1 is intrinsically cold- and chemosensitive with and without its
RT N-terminal ankyrin repeat domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:16901-16906(2014).
RN [9]
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-620; CYS-621 AND
RP CYS-665.
RX PubMed=27241698; DOI=10.1085/jgp.201611581;
RA Bahia P.K., Parks T.A., Stanford K.R., Mitchell D.A., Varma S.,
RA Stevens S.M. Jr., Taylor-Clark T.E.;
RT "The exceptionally high reactivity of Cys 621 is critical for electrophilic
RT activation of the sensory nerve ion channel TRPA1.";
RL J. Gen. Physiol. 147:451-465(2016).
RN [10]
RP MUTAGENESIS OF PRO-622; MET-634 AND THR-646, AND SUBUNIT.
RX PubMed=31447178; DOI=10.1016/j.cell.2019.07.014;
RA Lin King J.V., Emrick J.J., Kelly M.J.S., Herzig V., King G.F.,
RA Medzihradszky K.F., Julius D.;
RT "A cell-penetrating scorpion toxin enables mode-specific modulation of
RT TRPA1 and pain.";
RL Cell 178:1362-1374(2019).
RN [11]
RP MUTAGENESIS OF CYS-621; PHE-909 AND PHE-944, AND ACTIVITY REGULATION.
RX PubMed=30878828; DOI=10.1016/j.ejmech.2019.02.074;
RA Chandrabalan A., McPhillie M.J., Morice A.H., Boa A.N., Sadofsky L.R.;
RT "N-Cinnamoylanthranilates as human TRPA1 modulators: structure-activity
RT relationships and channel binding sites.";
RL Eur. J. Med. Chem. 170:141-156(2019).
RN [12]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.24 ANGSTROMS) IN COMPLEXES WITH
RP SYNTHETIC AGONISTS, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, DOMAIN, AND
RP MUTAGENESIS OF PHE-909.
RX PubMed=25855297; DOI=10.1038/nature14367;
RA Paulsen C.E., Armache J.P., Gao Y., Cheng Y., Julius D.;
RT "Structure of the TRPA1 ion channel suggests regulatory mechanisms.";
RL Nature 520:511-517(2015).
RN [13]
RP ERRATUM OF PUBMED:25855297.
RX PubMed=26200340; DOI=10.1038/nature14871;
RA Paulsen C.E., Armache J.P., Gao Y., Cheng Y., Julius D.;
RL Nature 525:552-552(2015).
RN [14]
RP VARIANT FEPS1 SER-855, CHARACTERIZATION OF VARIANT FEPS1 SER-855, FUNCTION,
RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=20547126; DOI=10.1016/j.neuron.2010.04.030;
RA Kremeyer B., Lopera F., Cox J.J., Momin A., Rugiero F., Marsh S.,
RA Woods C.G., Jones N.G., Paterson K.J., Fricker F.R., Villegas A.,
RA Acosta N., Pineda-Trujillo N.G., Ramirez J.D., Zea J., Burley M.W.,
RA Bedoya G., Bennett D.L., Wood J.N., Ruiz-Linares A.;
RT "A gain-of-function mutation in TRPA1 causes familial episodic pain
RT syndrome.";
RL Neuron 66:671-680(2010).
CC -!- FUNCTION: Receptor-activated non-selective cation channel involved in
CC pain detection and possibly also in cold perception, oxygen
CC concentration perception, cough, itch, and inner ear function
CC (PubMed:21873995, PubMed:23199233, PubMed:25389312, PubMed:25855297).
CC Shows 8-fold preference for divalent over monovalent cations
CC (PubMed:31447178). Has a central role in the pain response to
CC endogenous inflammatory mediators and to a diverse array of irritants,
CC such as allylthiocyanate (AITC) from mustard oil or wasabi,
CC cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein, an
CC irritant from tears gas and vehicle exhaust fumes (PubMed:25389312,
CC PubMed:27241698, PubMed:30878828, PubMed:20547126). Acts also as an
CC ionotropic cannabinoid receptor by being activated by delta(9)-
CC tetrahydrocannabinol (THC), the psychoactive component of marijuana
CC (PubMed:25389312). Is activated by a large variety of structurally
CC unrelated electrophilic and non-electrophilic chemical compounds.
CC Electrophilic ligands activate TRPA1 by interacting with critical N-
CC terminal Cys residues in a covalent manner, whereas mechanisms of non-
CC electrophilic ligands are not well determined. May be a component for
CC the mechanosensitive transduction channel of hair cells in inner ear,
CC thereby participating in the perception of sounds. Probably operated by
CC a phosphatidylinositol second messenger system (By similarity).
CC {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:20547126,
CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:25389312,
CC ECO:0000269|PubMed:25855297, ECO:0000269|PubMed:27241698,
CC ECO:0000269|PubMed:30878828, ECO:0000269|PubMed:31447178,
CC ECO:0000305|PubMed:23199233}.
CC -!- ACTIVITY REGULATION: A cytosolic factor (probably pyrophosphate,
CC polytriphosphate, polyP4, polyP25, polyP45, and/or polyP65) is
CC necessary for TRPA1 activation by irritants (PubMed:17567811). Such
CC factor acts by keeping TRPA1 in a agonist-sensitive state
CC (PubMed:17567811). Inhibited by the potent blocker of TRPV channels
CC ruthenium red, A-967079, AP-18, HC-030031, and aryl sulfonamide
CC derivative (S)-N-(4-chlorobenzyl)-1-((4-
CC fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide (ASD) (PubMed:17567811,
CC PubMed:21873995, PubMed:21402443, PubMed:30878828, PubMed:20547126).
CC Non-covalently activated by the scorpion wasabi receptor toxin
CC (PubMed:31447178). Activated by benzyl isothiocyanate (BITC),
CC iodoacetamide, sulfhydryl reactive agent MTSEA, N-methyl maleimide
CC (NMM), N-ethylmaleimide (NEM), and 2-aminoethyldiphenylborinate (2-APB)
CC (PubMed:17164327, PubMed:17567811, PubMed:21873995, PubMed:27241698).
CC Also activated by hyperoxia (PubMed:21873995).
CC {ECO:0000269|PubMed:17164327, ECO:0000269|PubMed:17567811,
CC ECO:0000269|PubMed:20547126, ECO:0000269|PubMed:21402443,
CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698,
CC ECO:0000269|PubMed:30878828, ECO:0000269|PubMed:31447178}.
CC -!- SUBUNIT: Homotetramer (PubMed:25389312, PubMed:25855297). Interacts
CC with TMEM100 (By similarity). Interacts with EGLN1 (By similarity).
CC Interacts with the scorpion wasabi receptor toxin at the same site that
CC electrophiles but in a non-covalent manner (PubMed:31447178).
CC {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:25389312,
CC ECO:0000269|PubMed:25855297, ECO:0000269|PubMed:31447178}.
CC -!- INTERACTION:
CC O75762; O75762: TRPA1; NbExp=2; IntAct=EBI-11722999, EBI-11722999;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20547126,
CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:25389312,
CC ECO:0000269|PubMed:25855297}; Multi-pass membrane protein
CC {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed at very low levels in fibroblasts.
CC {ECO:0000269|PubMed:10066796}.
CC -!- DEVELOPMENTAL STAGE: Expressed in embryos at 12 weeks of age.
CC {ECO:0000269|PubMed:10066796}.
CC -!- DOMAIN: C-terminal helices from the four subunits associate to form
CC atypical coiled coil structure; this region is probably involved in
CC binding the inositol polyphosphates that are required for optimal
CC channel activity (in vitro). {ECO:0000305|PubMed:25855297}.
CC -!- DOMAIN: The ANK repeat domain consists of a convex stem structure
CC formed by five ANK repeats and 11 additional ANK repeats that form a
CC crescent-shaped structure that surrounds the protein core.
CC {ECO:0000269|PubMed:25855297}.
CC -!- PTM: TRPA1 activation by electrophiles occurs though covalent
CC modification of specific cysteine residues in the N-terminal
CC cytoplasmic domain (PubMed:25389312). {ECO:0000305|PubMed:25389312}.
CC -!- PTM: Hydroxylation is required for TRPA1 activity inhibition in
CC normoxia. In hypoxia, the decrease in oxygen concentration diminishes
CC the activity of the hydroxylase EGLN1, thus relieving TRPA1 from
CC inhibition and ultimately leading to channel activation.
CC {ECO:0000269|PubMed:21873995}.
CC -!- PTM: Oxidation of Cys-633 and Cys-856 in hyperoxia may override the
CC hydroxylase EGLN1-mediated inhibition, causing TRPA1 activation.
CC {ECO:0000269|PubMed:21873995}.
CC -!- DISEASE: Episodic pain syndrome, familial, 1 (FEPS1) [MIM:615040]: An
CC autosomal dominant neurologic disorder characterized by onset in
CC infancy of episodic debilitating upper body pain triggered by fasting,
CC cold, and physical stress. The period of intense pain is accompanied by
CC breathing difficulties, tachycardia, sweating, generalized pallor,
CC peribuccal cyanosis, and stiffness of the abdominal wall. Affected
CC individuals do not manifest altered pain sensitivity outside the
CC episodes. {ECO:0000269|PubMed:20547126}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The power behind pain
CC - Issue 82 of May 2007;
CC URL="https://web.expasy.org/spotlight/back_issues/082";
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DR EMBL; Y10601; CAA71610.1; -; mRNA.
DR EMBL; AC022867; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS34908.1; -.
DR RefSeq; NP_015628.2; NM_007332.2.
DR RefSeq; XP_011515927.1; XM_011517625.2.
DR RefSeq; XP_016869435.1; XM_017013946.1.
DR PDB; 3J9P; EM; 4.24 A; A/B/C/D=2-1119.
DR PDB; 6HC8; X-ray; 1.90 A; E=313-339.
DR PDB; 6PQO; EM; 2.88 A; A/B/C/D=2-1119.
DR PDB; 6PQP; EM; 3.06 A; A/B/C/D=2-1119.
DR PDB; 6PQQ; EM; 2.81 A; A/B/C/D=2-1119.
DR PDB; 6V9V; EM; 2.60 A; A/B/C/D=1-1119.
DR PDB; 6V9W; EM; 3.10 A; A/B/C/D=1-1119.
DR PDB; 6V9X; EM; 3.30 A; A/B/C/D=1-1119.
DR PDB; 6V9Y; EM; 3.60 A; A/B/C/D=1-1119.
DR PDB; 6WJ5; EM; 3.60 A; A/B/C/D=448-1078.
DR PDB; 6X2J; EM; 3.00 A; A/B/C/D=448-1078.
DR PDB; 7JUP; EM; 3.05 A; A/B/C/D=448-1078.
DR PDBsum; 3J9P; -.
DR PDBsum; 6HC8; -.
DR PDBsum; 6PQO; -.
DR PDBsum; 6PQP; -.
DR PDBsum; 6PQQ; -.
DR PDBsum; 6V9V; -.
DR PDBsum; 6V9W; -.
DR PDBsum; 6V9X; -.
DR PDBsum; 6V9Y; -.
DR PDBsum; 6WJ5; -.
DR PDBsum; 6X2J; -.
DR PDBsum; 7JUP; -.
DR AlphaFoldDB; O75762; -.
DR SMR; O75762; -.
DR BioGRID; 114471; 6.
DR DIP; DIP-61520N; -.
DR IntAct; O75762; 3.
DR MINT; O75762; -.
DR STRING; 9606.ENSP00000262209; -.
DR BindingDB; O75762; -.
DR ChEMBL; CHEMBL6007; -.
DR DrugBank; DB11345; (S)-camphor.
DR DrugBank; DB11148; Butamben.
DR DrugBank; DB01744; Camphor.
DR DrugBank; DB09061; Cannabidiol.
DR DrugBank; DB14050; Cannabidivarin.
DR DrugBank; DB00825; Levomenthol.
DR DrugBank; DB14009; Medical Cannabis.
DR DrugBank; DB14011; Nabiximols.
DR DrugBank; DB11755; Tetrahydrocannabivarin.
DR DrugCentral; O75762; -.
DR GuidetoPHARMACOLOGY; 485; -.
DR TCDB; 1.A.4.6.3; the transient receptor potential ca(2+) channel (trp-cc) family.
DR GlyGen; O75762; 2 sites.
DR iPTMnet; O75762; -.
DR PhosphoSitePlus; O75762; -.
DR BioMuta; TRPA1; -.
DR jPOST; O75762; -.
DR MassIVE; O75762; -.
DR PaxDb; O75762; -.
DR PeptideAtlas; O75762; -.
DR PRIDE; O75762; -.
DR ProteomicsDB; 50181; -.
DR Antibodypedia; 12262; 294 antibodies from 33 providers.
DR DNASU; 8989; -.
DR Ensembl; ENST00000262209.5; ENSP00000262209.4; ENSG00000104321.11.
DR GeneID; 8989; -.
DR KEGG; hsa:8989; -.
DR MANE-Select; ENST00000262209.5; ENSP00000262209.4; NM_007332.3; NP_015628.2.
DR UCSC; uc003xza.4; human.
DR CTD; 8989; -.
DR DisGeNET; 8989; -.
DR GeneCards; TRPA1; -.
DR HGNC; HGNC:497; TRPA1.
DR HPA; ENSG00000104321; Tissue enhanced (intestine, stomach, urinary bladder).
DR MalaCards; TRPA1; -.
DR MIM; 604775; gene.
DR MIM; 615040; phenotype.
DR neXtProt; NX_O75762; -.
DR OpenTargets; ENSG00000104321; -.
DR Orphanet; 581271; Cramp-fasciculation syndrome.
DR Orphanet; 391389; Familial episodic pain syndrome with predominantly upper body involvement.
DR VEuPathDB; HostDB:ENSG00000104321; -.
DR eggNOG; KOG0510; Eukaryota.
DR GeneTree; ENSGT00940000156118; -.
DR InParanoid; O75762; -.
DR OMA; HWATEKN; -.
DR OrthoDB; 361612at2759; -.
DR PhylomeDB; O75762; -.
DR TreeFam; TF317264; -.
DR PathwayCommons; O75762; -.
DR Reactome; R-HSA-3295583; TRP channels.
DR SignaLink; O75762; -.
DR BioGRID-ORCS; 8989; 6 hits in 1065 CRISPR screens.
DR GenomeRNAi; 8989; -.
DR Pharos; O75762; Tclin.
DR PRO; PR:O75762; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; O75762; protein.
DR Bgee; ENSG00000104321; Expressed in oocyte and 109 other tissues.
DR ExpressionAtlas; O75762; baseline and differential.
DR Genevisible; O75762; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032421; C:stereocilium bundle; IEA:Ensembl.
DR GO; GO:0005262; F:calcium channel activity; TAS:Reactome.
DR GO; GO:0015278; F:calcium-release channel activity; IDA:UniProtKB.
DR GO; GO:0015267; F:channel activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0097604; F:temperature-gated cation channel activity; IDA:UniProtKB.
DR GO; GO:0070588; P:calcium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IDA:MGI.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:MGI.
DR GO; GO:0071310; P:cellular response to organic substance; IEA:Ensembl.
DR GO; GO:0050968; P:detection of chemical stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl.
DR GO; GO:0006811; P:ion transport; TAS:ProtInc.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0010033; P:response to organic substance; IMP:UniProtKB.
DR GO; GO:0048265; P:response to pain; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IMP:UniProtKB.
DR GO; GO:0050955; P:thermoception; IEA:Ensembl.
DR Gene3D; 1.25.40.20; -; 5.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR005821; Ion_trans_dom.
DR Pfam; PF00023; Ank; 1.
DR Pfam; PF12796; Ank_2; 6.
DR Pfam; PF00520; Ion_trans; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 14.
DR SUPFAM; SSF48403; SSF48403; 2.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 9.
PE 1: Evidence at protein level;
KW 3D-structure; ANK repeat; Cell membrane; Coiled coil; Disease variant;
KW Disulfide bond; Glycoprotein; Hydroxylation; Ion channel; Ion transport;
KW Membrane; Oxidation; Reference proteome; Repeat; Sensory transduction;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1119
FT /note="Transient receptor potential cation channel
FT subfamily A member 1"
FT /id="PRO_0000215369"
FT TOPO_DOM 1..719
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 720..740
FT /note="Helical; Name=1"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 741..764
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 765..785
FT /note="Helical; Name=2"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 786..803
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 804..824
FT /note="Helical; Name=3"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 825..829
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 830..850
FT /note="Helical; Name=4"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 851..873
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 874..894
FT /note="Helical; Name=5"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 895..901
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:25855297"
FT INTRAMEM 902..922
FT /note="Pore-forming"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 923..934
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TRANSMEM 935..956
FT /note="Helical; Name=6"
FT /evidence="ECO:0000305|PubMed:25855297"
FT TOPO_DOM 957..1119
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25855297"
FT REPEAT 62..92
FT /note="ANK 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 97..126
FT /note="ANK 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 130..160
FT /note="ANK 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 164..193
FT /note="ANK 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 197..226
FT /note="ANK 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 238..267
FT /note="ANK 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 271..301
FT /note="ANK 7"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 308..337
FT /note="ANK 8"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 341..370
FT /note="ANK 9"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 374..403
FT /note="ANK 10"
FT /evidence="ECO:0000305|PubMed:25855297"
FT REPEAT 412..441
FT /note="ANK 11"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 445..474
FT /note="ANK 12"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 481..510
FT /note="ANK 13"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 513..542
FT /note="ANK 14"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 547..576
FT /note="ANK 15"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT REPEAT 579..609
FT /note="ANK 16"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297"
FT COILED 1042..1071
FT /evidence="ECO:0000305|PubMed:25855297"
FT BINDING 414
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT BINDING 421
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT BINDING 621
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent; Cys highly reactive"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8,
FT ECO:0000305|PubMed:17164327, ECO:0000305|PubMed:27241698"
FT BINDING 641
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent"
FT /evidence="ECO:0000305|PubMed:17164327"
FT BINDING 665
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent"
FT /evidence="ECO:0000305|PubMed:17164327,
FT ECO:0000305|PubMed:27241698"
FT BINDING 710
FT /ligand="(E)-cinnamaldehyde"
FT /ligand_id="ChEBI:CHEBI:16731"
FT /ligand_note="agonist"
FT /note="covalent"
FT /evidence="ECO:0000305|PubMed:17164327"
FT BINDING 1046..1052
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
FT inositol)"
FT /ligand_id="ChEBI:CHEBI:57880"
FT /evidence="ECO:0000305|PubMed:25855297"
FT SITE 620
FT /note="Required for C-621 reactivity"
FT /evidence="ECO:0000269|PubMed:27241698"
FT SITE 622
FT /note="Key residue for activation by the scorpion wasabi
FT receptor toxin"
FT /evidence="ECO:0000269|PubMed:31447178"
FT SITE 634
FT /note="Important residue for activation by the scorpion
FT wasabi receptor toxin"
FT /evidence="ECO:0000269|PubMed:31447178"
FT SITE 646
FT /note="Important residue for activation by the scorpion
FT wasabi receptor toxin"
FT /evidence="ECO:0000269|PubMed:31447178"
FT MOD_RES 394
FT /note="4-hydroxyproline; by EGLN1; transient; in normoxia
FT and hyperoxia"
FT /evidence="ECO:0000269|PubMed:21873995"
FT MOD_RES 633
FT /note="Cysteine sulfenic acid (-SOH); transient; in
FT hyperoxia"
FT /evidence="ECO:0000305|PubMed:21873995"
FT MOD_RES 856
FT /note="Cysteine sulfenic acid (-SOH); transient; in
FT hyperoxia"
FT /evidence="ECO:0000305|PubMed:21873995"
FT CARBOHYD 747
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 753
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 192..665
FT /note="Alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT DISULFID 462..665
FT /note="Alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT DISULFID 608..621
FT /note="Alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT DISULFID 621..665
FT /note="Alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8BLA8"
FT DISULFID 633..856
FT /note="Alternate; transient; in hyperoxia; unknown whether
FT inter- or intrachain"
FT /evidence="ECO:0000305|PubMed:21873995"
FT VARIANT 3
FT /note="R -> C (in dbSNP:rs13268757)"
FT /evidence="ECO:0000269|PubMed:10066796"
FT /id="VAR_020660"
FT VARIANT 58
FT /note="R -> T (in dbSNP:rs16937976)"
FT /evidence="ECO:0000269|PubMed:10066796"
FT /id="VAR_047471"
FT VARIANT 179
FT /note="E -> K (in dbSNP:rs920829)"
FT /id="VAR_020661"
FT VARIANT 186
FT /note="K -> N (in dbSNP:rs7819749)"
FT /evidence="ECO:0000269|PubMed:10066796"
FT /id="VAR_020662"
FT VARIANT 855
FT /note="N -> S (in FEPS1; 5-fold increase in inward current
FT when stimulated by the agonist cinnamaldehyde compared to
FT wild-type at normal neuronal resting potential; consistent
FT with a gain of function mutation; dbSNP:rs398123010)"
FT /evidence="ECO:0000269|PubMed:20547126"
FT /id="VAR_069737"
FT VARIANT 1018
FT /note="H -> R (in dbSNP:rs959976)"
FT /id="VAR_020663"
FT MUTAGEN 173
FT /note="C->S: Decrease in activation by hyperoxia and
FT diallyl disulfide."
FT /evidence="ECO:0000269|PubMed:21873995"
FT MUTAGEN 192
FT /note="C->S: Decrease in activation by hyperoxia and
FT diallyl disulfide."
FT /evidence="ECO:0000269|PubMed:21873995"
FT MUTAGEN 394
FT /note="P->A: Loss of answer to hypoxia and hydroxylase
FT inhibitor DMOG, but not to AITC and hyperoxia."
FT /evidence="ECO:0000269|PubMed:21873995"
FT MUTAGEN 620
FT /note="K->A: Important decrease in electrophile-evoked
FT response."
FT /evidence="ECO:0000269|PubMed:27241698"
FT MUTAGEN 621
FT /note="C->A,S: Decrease in electrophile-evoked response. No
FT change in answer to hyperoxia and diallyl disulfide. In
FT TRPA1-3C-K708R/Q; loss in irritant-evoked response."
FT /evidence="ECO:0000269|PubMed:17164327,
FT ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698,
FT ECO:0000269|PubMed:30878828"
FT MUTAGEN 622
FT /note="P->A: Loss of activation by the scorpion wasabi
FT receptor toxin."
FT /evidence="ECO:0000269|PubMed:31447178"
FT MUTAGEN 633
FT /note="C->S: Decrease in activation by hyperoxia and
FT diallyl disulfide. Important decrease in activation by
FT hyperoxia and diallyl disulfide; when associated with S-
FT 856."
FT /evidence="ECO:0000269|PubMed:21873995"
FT MUTAGEN 634
FT /note="M->L: Loss of activation by the scorpion wasabi
FT receptor toxin."
FT /evidence="ECO:0000269|PubMed:31447178"
FT MUTAGEN 641
FT /note="C->A,S: Decrease in electrophile-evoked and
FT hyperoxia response. In TRPA1-3C-K708R/Q; loss in irritant-
FT evoked response."
FT /evidence="ECO:0000269|PubMed:17164327,
FT ECO:0000269|PubMed:21873995"
FT MUTAGEN 646
FT /note="T->P: Loss of activation by the scorpion wasabi
FT receptor toxin."
FT /evidence="ECO:0000269|PubMed:31447178"
FT MUTAGEN 665
FT /note="C->A,L,S: Decrease in electrophile-evoked and
FT hyperoxia response. In TRPA1-3C-K708R/Q; loss in irritant-
FT evoked response."
FT /evidence="ECO:0000269|PubMed:17164327,
FT ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698"
FT MUTAGEN 710
FT /note="K->R,Q: No change in electrophile sensitivity. In
FT TRPA1-3C-K708R/Q; loss in irritant-evoked response."
FT MUTAGEN 856
FT /note="C->S: Decrease in activation by hyperoxia and
FT diallyl disulfide. Important decrease in activation by
FT hyperoxia and diallyl disulfide; when associated with S-
FT 633."
FT /evidence="ECO:0000269|PubMed:21873995"
FT MUTAGEN 909
FT /note="F->A,T: Loss of inhibition by A-967079, AP-18, and
FT ASD. Increase in activation by cinnamaldehyde, AITC and
FT acrolein."
FT /evidence="ECO:0000269|PubMed:25855297,
FT ECO:0000269|PubMed:30878828"
FT MUTAGEN 944
FT /note="F->A: Loss of inhibition by A-967079, AP-18, and
FT ASD. Weak or no change in activation by cinnamaldehyde,
FT AITC and acrolein."
FT /evidence="ECO:0000269|PubMed:30878828"
FT HELIX 325..329
FT /evidence="ECO:0007829|PDB:6HC8"
FT HELIX 448..455
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 459..466
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 473..475
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 485..491
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 495..504
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 512..514
FT /evidence="ECO:0007829|PDB:6V9W"
FT HELIX 517..522
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 523..525
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 527..533
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 538..540
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 551..557
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 561..569
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 578..580
FT /evidence="ECO:0007829|PDB:6V9X"
FT HELIX 583..589
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 593..601
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 602..604
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 605..609
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 617..619
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 622..628
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 631..641
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 642..647
FT /evidence="ECO:0007829|PDB:6PQO"
FT STRAND 650..653
FT /evidence="ECO:0007829|PDB:6PQP"
FT STRAND 656..659
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 661..663
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 668..670
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 673..676
FT /evidence="ECO:0007829|PDB:6PQP"
FT HELIX 684..691
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 695..698
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 701..713
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 715..739
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 742..744
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 750..752
FT /evidence="ECO:0007829|PDB:6PQO"
FT HELIX 767..794
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 795..799
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 804..818
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 820..822
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 828..849
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 851..856
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 857..871
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 874..891
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 892..894
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 898..900
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 901..910
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 911..913
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 919..922
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 923..927
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 934..947
FT /evidence="ECO:0007829|PDB:6V9V"
FT TURN 948..950
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 951..969
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 971..989
FT /evidence="ECO:0007829|PDB:6V9V"
FT HELIX 992..998
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 1001..1005
FT /evidence="ECO:0007829|PDB:6V9V"
FT STRAND 1007..1009
FT /evidence="ECO:0007829|PDB:6PQQ"
FT HELIX 1016..1024
FT /evidence="ECO:0007829|PDB:6PQQ"
FT HELIX 1041..1070
FT /evidence="ECO:0007829|PDB:6V9V"
SQ SEQUENCE 1119 AA; 127501 MW; 283BF31BC77CF71B CRC64;
MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD
DMDTFFLHYA AAEGQIELME KITRDSSLEV LHEMDDYGNT PLHCAVEKNQ IESVKFLLSR
GANPNLRNFN MMAPLHIAVQ GMNNEVMKVL LEHRTIDVNL EGENGNTAVI IACTTNNSEA
LQILLKKGAK PCKSNKWGCF PIHQAAFSGS KECMEIILRF GEEHGYSRQL HINFMNNGKA
TPLHLAVQNG DLEMIKMCLD NGAQIDPVEK GRCTAIHFAA TQGATEIVKL MISSYSGSVD
IVNTTDGCHE TMLHRASLFD HHELADYLIS VGADINKIDS EGRSPLILAT ASASWNIVNL
LLSKGAQVDI KDNFGRNFLH LTVQQPYGLK NLRPEFMQMQ QIKELVMDED NDGCTPLHYA
CRQGGPGSVN NLLGFNVSIH SKSKDKKSPL HFAASYGRIN TCQRLLQDIS DTRLLNEGDL
HGMTPLHLAA KNGHDKVVQL LLKKGALFLS DHNGWTALHH ASMGGYTQTM KVILDTNLKC
TDRLDEDGNT ALHFAAREGH AKAVALLLSH NADIVLNKQQ ASFLHLALHN KRKEVVLTII
RSKRWDECLK IFSHNSPGNK CPITEMIEYL PECMKVLLDF CMLHSTEDKS CRDYYIEYNF
KYLQCPLEFT KKTPTQDVIY EPLTALNAMV QNNRIELLNH PVCKEYLLMK WLAYGFRAHM
MNLGSYCLGL IPMTILVVNI KPGMAFNSTG IINETSDHSE ILDTTNSYLI KTCMILVFLS
SIFGYCKEAG QIFQQKRNYF MDISNVLEWI IYTTGIIFVL PLFVEIPAHL QWQCGAIAVY
FYWMNFLLYL QRFENCGIFI VMLEVILKTL LRSTVVFIFL LLAFGLSFYI LLNLQDPFSS
PLLSIIQTFS MMLGDINYRE SFLEPYLRNE LAHPVLSFAQ LVSFTIFVPI VLMNLLIGLA
VGDIAEVQKH ASLKRIAMQV ELHTSLEKKL PLWFLRKVDQ KSTIVYPNKP RSGGMLFHIF
CFLFCTGEIR QEIPNADKSL EMEILKQKYR LKDLTFLLEK QHELIKLIIQ KMEIISETED
DDSHCSFQDR FKKEQMEQRN SRWNTVLRAV KAKTHHLEP
