ID   TRHDE_HUMAN             Reviewed;        1024 AA.
AC   Q9UKU6; A5PL19; Q6UWJ4;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   08-NOV-2023, entry version 184.
DE   RecName: Full=Thyrotropin-releasing hormone-degrading ectoenzyme;
DE            Short=TRH-DE;
DE            Short=TRH-degrading ectoenzyme;
DE            EC=3.4.19.6;
DE   AltName: Full=Pyroglutamyl-peptidase II;
DE            Short=PAP-II;
DE   AltName: Full=TRH-specific aminopeptidase;
DE   AltName: Full=Thyroliberinase;
GN   Name=TRHDE; ORFNames=UNQ2507/PRO5995;
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].
RC   TISSUE=Lung;
RX   PubMed=10491199; DOI=10.1046/j.1432-1327.1999.00753.x;
RA   Schomburg L., Turwitt S., Prescher G., Lohmann D., Horsthemke B., Bauer K.;
RT   "Human TRH-degrading ectoenzyme cDNA cloning, functional expression,
RT   genomic structure and chromosomal assignment.";
RL   Eur. J. Biochem. 265:415-422(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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).
CC   -!- FUNCTION: Specific inactivation of TRH after its release.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of the N-terminal pyroglutamyl group from pGlu-|-His-
CC         Xaa tripeptides and pGlu-|-His-Xaa-Gly tetrapeptides.; EC=3.4.19.6;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC   -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Membrane; Single-pass type II membrane protein.
CC   -!- TISSUE SPECIFICITY: Predominantly expressed in brain.
CC   -!- SIMILARITY: Belongs to the peptidase M1 family. {ECO:0000305}.
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DR   EMBL; AF126372; AAF13141.1; -; mRNA.
DR   EMBL; AY358765; AAQ89125.1; -; mRNA.
DR   EMBL; BC142706; AAI42707.1; -; mRNA.
DR   EMBL; BC150181; AAI50182.1; -; mRNA.
DR   RefSeq; NP_037513.1; NM_013381.2.
DR   AlphaFoldDB; Q9UKU6; -.
DR   SMR; Q9UKU6; -.
DR   BioGRID; 118990; 135.
DR   IntAct; Q9UKU6; 16.
DR   STRING; 9606.ENSP00000261180; -.
DR   ChEMBL; CHEMBL3886123; -.
DR   MEROPS; M01.008; -.
DR   GlyCosmos; Q9UKU6; 13 sites, 1 glycan.
DR   GlyGen; Q9UKU6; 14 sites, 2 O-linked glycans (2 sites).
DR   iPTMnet; Q9UKU6; -.
DR   PhosphoSitePlus; Q9UKU6; -.
DR   BioMuta; TRHDE; -.
DR   DMDM; 11387208; -.
DR   jPOST; Q9UKU6; -.
DR   MassIVE; Q9UKU6; -.
DR   PaxDb; 9606-ENSP00000261180; -.
DR   PeptideAtlas; Q9UKU6; -.
DR   ProteomicsDB; 84878; -.
DR   Antibodypedia; 52788; 88 antibodies from 14 providers.
DR   DNASU; 29953; -.
DR   Ensembl; ENST00000261180.10; ENSP00000261180.5; ENSG00000072657.10.
DR   GeneID; 29953; -.
DR   KEGG; hsa:29953; -.
DR   MANE-Select; ENST00000261180.10; ENSP00000261180.5; NM_013381.3; NP_037513.2.
DR   UCSC; uc001sxa.4; human.
DR   AGR; HGNC:30748; -.
DR   CTD; 29953; -.
DR   DisGeNET; 29953; -.
DR   GeneCards; TRHDE; -.
DR   HGNC; HGNC:30748; TRHDE.
DR   HPA; ENSG00000072657; Tissue enhanced (adipose tissue, pancreas).
DR   MIM; 606950; gene.
DR   neXtProt; NX_Q9UKU6; -.
DR   PharmGKB; PA142670702; -.
DR   VEuPathDB; HostDB:ENSG00000072657; -.
DR   eggNOG; KOG1046; Eukaryota.
DR   HOGENOM; CLU_003705_2_2_1; -.
DR   InParanoid; Q9UKU6; -.
DR   OMA; ANVHWKM; -.
DR   OrthoDB; 3085317at2759; -.
DR   PhylomeDB; Q9UKU6; -.
DR   TreeFam; TF300395; -.
DR   PathwayCommons; Q9UKU6; -.
DR   SignaLink; Q9UKU6; -.
DR   BioGRID-ORCS; 29953; 12 hits in 1152 CRISPR screens.
DR   ChiTaRS; TRHDE; human.
DR   GenomeRNAi; 29953; -.
DR   Pharos; Q9UKU6; Tbio.
DR   PRO; PR:Q9UKU6; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; Q9UKU6; Protein.
DR   Bgee; ENSG00000072657; Expressed in jejunal mucosa and 139 other tissues.
DR   ExpressionAtlas; Q9UKU6; baseline and differential.
DR   Genevisible; Q9UKU6; HS.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR   GO; GO:0004177; F:aminopeptidase activity; TAS:ProtInc.
DR   GO; GO:0070006; F:metalloaminopeptidase activity; IBA:GO_Central.
DR   GO; GO:0042277; F:peptide binding; IBA:GO_Central.
DR   GO; GO:0016920; F:pyroglutamyl-peptidase activity; IEA:UniProtKB-EC.
DR   GO; GO:0008270; F:zinc ion binding; IBA:GO_Central.
DR   GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR   GO; GO:0043171; P:peptide catabolic process; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   CDD; cd09601; M1_APN-Q_like; 1.
DR   Gene3D; 1.25.50.20; -; 1.
DR   Gene3D; 2.60.40.1910; -; 1.
DR   Gene3D; 1.10.390.10; Neutral Protease Domain 2; 1.
DR   Gene3D; 2.60.40.1730; tricorn interacting facor f3 domain; 1.
DR   InterPro; IPR045357; Aminopeptidase_N-like_N.
DR   InterPro; IPR042097; Aminopeptidase_N-like_N_sf.
DR   InterPro; IPR024571; ERAP1-like_C_dom.
DR   InterPro; IPR034016; M1_APN-typ.
DR   InterPro; IPR001930; Peptidase_M1.
DR   InterPro; IPR014782; Peptidase_M1_dom.
DR   InterPro; IPR027268; Peptidase_M4/M1_CTD_sf.
DR   PANTHER; PTHR11533; PROTEASE M1 ZINC METALLOPROTEASE; 1.
DR   PANTHER; PTHR11533:SF40; THYROTROPIN-RELEASING HORMONE-DEGRADING ECTOENZYME; 1.
DR   Pfam; PF11838; ERAP1_C; 1.
DR   Pfam; PF01433; Peptidase_M1; 1.
DR   Pfam; PF17900; Peptidase_M1_N; 1.
DR   PRINTS; PR00756; ALADIPTASE.
DR   SUPFAM; SSF63737; Leukotriene A4 hydrolase N-terminal domain; 1.
DR   SUPFAM; SSF55486; Metalloproteases ('zincins'), catalytic domain; 1.
DR   PROSITE; PS00142; ZINC_PROTEASE; 1.
PE   2: Evidence at transcript level;
KW   Aminopeptidase; Disulfide bond; Glycoprotein; Hydrolase; Membrane;
KW   Metal-binding; Metalloprotease; Protease; Reference proteome;
KW   Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT   CHAIN           1..1024
FT                   /note="Thyrotropin-releasing hormone-degrading ectoenzyme"
FT                   /id="PRO_0000095118"
FT   TOPO_DOM        1..40
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        41..61
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        62..1024
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   REGION          72..135
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        441
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         404..408
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         440
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         444
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         463
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   SITE            527
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        89
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        160
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        175
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        222
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        338
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        605
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        634
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        649
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        663
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        684
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        800
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        906
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        68
FT                   /note="Interchain"
FT                   /evidence="ECO:0000250"
FT   CONFLICT        958
FT                   /note="N -> Y (in Ref. 2; AAQ89125)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1024 AA;  117000 MW;  B82FBBC93927F6DC CRC64;
     MGEDDAALRA GSRGLSDPWA DSVGVRPRTT ERHIAVHKRL VLAFAVSLVA LLAVTMLAVL
     LSLRFDECGA SATPGADGGP SGFPERGGNG SLPGSARRNH HAGGDSWQPE AGGVASPGTT
     SAQPPSEEER EPWEPWTQLR LSGHLKPLHY NLMLTAFMEN FTFSGEVNVE IACRNATRYV
     VLHASRVAVE KVQLAEDRAF GAVPVAGFFL YPQTQVLVVV LNRTLDAQRN YNLKIIYNAL
     IENELLGFFR SSYVLHGERR FLGVTQFSPT HARKAFPCFD EPIYKATFKI SIKHQATYLS
     LSNMPVETSV FEEDGWVTDH FSQTPLMSTY YLAWAICNFT YRETTTKSGV VVRLYARPDA
     IRRGSGDYAL HITKRLIEFY EDYFKVPYSL PKLDLLAVPK HPYAAMENWG LSIFVEQRIL
     LDPSVSSISY LLDVTMVIVH EICHQWFGDL VTPVWWEDVW LKEGFAHYFE FVGTDYLYPG
     WNMEKQRFLT DVLHEVMLLD GLASSHPVSQ EVLQATDIDR VFDWIAYKKG AALIRMLANF
     MGHSVFQRGL QDYLTIHKYG NAARNDLWNT LSEALKRNGK YVNIQEVMDQ WTLQMGYPVI
     TILGNTTAEN RIIITQQHFI YDISAKTKAL KLQNNSYLWQ IPLTIVVGNR SHVSSEAIIW
     VSNKSEHHRI TYLDKGSWLL GNINQTGYFR VNYDLRNWRL LIDQLIRNHE VLSVSNRAGL
     IDDAFSLARA GYLPQNIPLE IIRYLSEEKD FLPWHAASRA LYPLDKLLDR MENYNIFNEY
     ILKQVATTYI KLGWPKNNFN GSLVQASYQH EELRREVIML ACSFGNKHCH QQASTLISDW
     ISSNRNRIPL NVRDIVYCTG VSLLDEDVWE FIWMKFHSTT AVSEKKILLE ALTCSDDRNL
     LNRLLNLSLN SEVVLDQDAI DVIIHVARNP HGRDLAWKFF RDKWKILNTR YGEALFMNSK
     LISGVTEFLN TEGELKELKN FMKNYDGVAA ASFSRAVETV EANVRWKMLY QDELFQWLGK
     ALRH
//