ID   LCAP_RAT                Reviewed;        1025 AA.
AC   P97629; Q11009;
DT   27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1997, sequence version 1.
DT   27-MAR-2024, entry version 176.
DE   RecName: Full=Leucyl-cystinyl aminopeptidase;
DE            Short=Cystinyl aminopeptidase;
DE            EC=3.4.11.3;
DE   AltName: Full=GP160;
DE   AltName: Full=Insulin-regulated membrane aminopeptidase;
DE   AltName: Full=Insulin-responsive aminopeptidase;
DE            Short=IRAP;
DE   AltName: Full=Oxytocinase;
DE            Short=OTase;
DE   AltName: Full=Placental leucine aminopeptidase;
DE            Short=P-LAP;
DE   AltName: Full=Vesicle protein of 165 kDa;
DE            Short=Vp165;
GN   Name=Lnpep; Synonyms=Irap, Otase;
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], AND CHARACTERIZATION.
RC   STRAIN=Sprague-Dawley; TISSUE=Adipocyte;
RX   PubMed=7559527; DOI=10.1074/jbc.270.40.23612;
RA   Keller S.R., Scott H.M., Mastick C.C., Aebersold R., Lienhard G.E.;
RT   "Cloning and characterization of a novel insulin-regulated membrane
RT   aminopeptidase from Glut4 vesicles.";
RL   J. Biol. Chem. 270:23612-23618(1995).
RN   [2]
RP   PROTEIN SEQUENCE OF 168-176; 387-399; 731-740 AND 893-905.
RX   PubMed=8119954; DOI=10.1016/s0021-9258(17)37573-7;
RA   Mastick C.C., Aebersold R., Lienhard G.E.;
RT   "Characterization of a major protein in GLUT4 vesicles. Concentration in
RT   the vesicles and insulin-stimulated translocation to the plasma membrane.";
RL   J. Biol. Chem. 269:6089-6092(1994).
RN   [3]
RP   PHOSPHORYLATION AT SER-80 AND SER-91, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RX   PubMed=12061804; DOI=10.1016/s0003-9861(02)00261-8;
RA   Ryu J., Hah J.S., Park J.S.S., Lee W., Rampal A.L., Jung C.Y.;
RT   "Protein kinase C-zeta phosphorylates insulin-responsive aminopeptidase in
RT   vitro at Ser-80 and Ser-91.";
RL   Arch. Biochem. Biophys. 403:71-82(2002).
CC   -!- FUNCTION: Release of an N-terminal amino acid, cleave before cysteine,
CC       leucine as well as other amino acids. Degrades peptide hormones such as
CC       oxytocin, vasopressin and angiotensin III, and plays a role in
CC       maintaining homeostasis during pregnancy. May be involved in the
CC       inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin
CC       and dynorphin. Binds angiotensin IV and may be the angiotensin IV
CC       receptor in the brain (By similarity). {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of an N-terminal amino acid, Cys-|-Xaa-, in which the
CC         half-cystine residue is involved in a disulfide loop, notably in
CC         oxytocin or vasopressin. Hydrolysis rates on a range of aminoacyl
CC         arylamides exceed that for the cystinyl derivative, however.;
CC         EC=3.4.11.3;
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. Binds tankyrases 1 and 2 (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type II membrane
CC       protein. Endomembrane system; Single-pass type II membrane protein.
CC       Note=Localized mainly in intracellular vesicles together with GLUT4.
CC       Relocalizes to the plasma membrane in response to insulin. The
CC       dileucine internalization motif and/or the interaction with tankyrases
CC       may be involved in intracellular sequestration.
CC   -!- TISSUE SPECIFICITY: Highly expressed in heart, brain, spleen, lung,
CC       kidney and white adipose tissue. Detected at lower levels in skeletal
CC       muscle and liver.
CC   -!- PTM: N-glycosylated.
CC   -!- SIMILARITY: Belongs to the peptidase M1 family. {ECO:0000305}.
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DR   EMBL; U76997; AAB19066.1; -; mRNA.
DR   EMBL; U32990; AAB38021.1; -; mRNA.
DR   PIR; I55441; I55441.
DR   RefSeq; NP_001106874.1; NM_001113403.1.
DR   RefSeq; NP_598258.1; NM_133574.1.
DR   RefSeq; XP_008757040.1; XM_008758818.2.
DR   RefSeq; XP_017443357.1; XM_017587868.1.
DR   AlphaFoldDB; P97629; -.
DR   SMR; P97629; -.
DR   IntAct; P97629; 2.
DR   STRING; 10116.ENSRNOP00000069259; -.
DR   BindingDB; P97629; -.
DR   ChEMBL; CHEMBL3712; -.
DR   DrugCentral; P97629; -.
DR   MEROPS; M01.011; -.
DR   GlyCosmos; P97629; 17 sites, No reported glycans.
DR   GlyGen; P97629; 17 sites.
DR   iPTMnet; P97629; -.
DR   PhosphoSitePlus; P97629; -.
DR   SwissPalm; P97629; -.
DR   jPOST; P97629; -.
DR   PaxDb; 10116-ENSRNOP00000017718; -.
DR   Ensembl; ENSRNOT00000017718.7; ENSRNOP00000017718.6; ENSRNOG00000055229.2.
DR   GeneID; 171105; -.
DR   KEGG; rno:171105; -.
DR   UCSC; RGD:621752; rat.
DR   AGR; RGD:621752; -.
DR   CTD; 4012; -.
DR   RGD; 621752; Lnpep.
DR   eggNOG; KOG1046; Eukaryota.
DR   GeneTree; ENSGT00940000157902; -.
DR   HOGENOM; CLU_003705_2_2_1; -.
DR   InParanoid; P97629; -.
DR   OrthoDB; 3085317at2759; -.
DR   PhylomeDB; P97629; -.
DR   BRENDA; 3.4.11.3; 5301.
DR   Reactome; R-RNO-1236977; Endosomal/Vacuolar pathway.
DR   Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   PRO; PR:P97629; -.
DR   Proteomes; UP000002494; Chromosome 1.
DR   GO; GO:0009986; C:cell surface; IDA:RGD.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0030659; C:cytoplasmic vesicle membrane; ISO:RGD.
DR   GO; GO:0032593; C:insulin-responsive compartment; IDA:RGD.
DR   GO; GO:0016020; C:membrane; ISO:RGD.
DR   GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR   GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR   GO; GO:0031982; C:vesicle; IDA:RGD.
DR   GO; GO:0004177; F:aminopeptidase activity; IDA:RGD.
DR   GO; GO:0070006; F:metalloaminopeptidase activity; IBA:GO_Central.
DR   GO; GO:0042277; F:peptide binding; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IBA:GO_Central.
DR   GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR   GO; GO:0010813; P:neuropeptide catabolic process; IMP:RGD.
DR   GO; GO:0043171; P:peptide catabolic process; IDA:RGD.
DR   GO; GO:0045777; P:positive regulation of blood pressure; IMP:RGD.
DR   GO; GO:0030163; P:protein catabolic process; ISO:RGD.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   GO; GO:0008217; P:regulation of blood pressure; IBA:GO_Central.
DR   GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IMP:RGD.
DR   GO; GO:0009725; P:response to hormone; IDA:RGD.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
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:SF42; LEUCYL-CYSTINYL AMINOPEPTIDASE; 1.
DR   PANTHER; PTHR11533; PROTEASE M1 ZINC METALLOPROTEASE; 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.
DR   Genevisible; P97629; RN.
PE   1: Evidence at protein level;
KW   Acetylation; Aminopeptidase; Cell membrane; Direct protein sequencing;
KW   Glycoprotein; Hydrolase; Membrane; Metal-binding; Metalloprotease;
KW   Phosphoprotein; Protease; Reference proteome; Signal-anchor; Transmembrane;
KW   Transmembrane helix; Zinc.
FT   CHAIN           1..1025
FT                   /note="Leucyl-cystinyl aminopeptidase"
FT                   /id="PRO_0000095115"
FT   TOPO_DOM        1..109
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        110..131
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        132..1025
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   REGION          96..101
FT                   /note="Tankyrase binding"
FT                   /evidence="ECO:0000250"
FT   MOTIF           53..54
FT                   /note="Dileucine internalization motif"
FT                   /evidence="ECO:0000255"
FT   MOTIF           76..77
FT                   /note="Dileucine internalization motif"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        465
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         295
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         428..432
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         464
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         468
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   BINDING         487
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT   SITE            549
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UIQ6"
FT   MOD_RES         70
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8C129"
FT   MOD_RES         80
FT                   /note="Phosphoserine; by PKC/PRKCZ; in vitro"
FT                   /evidence="ECO:0000269|PubMed:12061804"
FT   MOD_RES         91
FT                   /note="Phosphoserine; by PKC/PRKCZ; in vitro"
FT                   /evidence="ECO:0000269|PubMed:12061804"
FT   CARBOHYD        145
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        184
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        215
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        256
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        266
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        368
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        374
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        447
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        525
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        578
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        664
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        682
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        695
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        758
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        834
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        850
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        989
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CONFLICT        909..916
FT                   /note="LMKSSLDG -> YGTTQRAW (in Ref. 1; AAB38021)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        916..1025
FT                   /note="Missing (in Ref. 1; AAB38021)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1025 AA;  117201 MW;  8AD3BA3A446FB5EF CRC64;
     METFTNDRLQ LPRNMIENSM FEEEPDVVDL AKEPCLHPLE PDEVEYEPRG SRLLVRGLGE
     HEMDEDEEDY ESSAKLLGMS FMNRSSGLRN SATGYRQSPD GTCSVPSART LVICVFVIVV
     AVSVIMVIYL LPRCTFTKEG CHKTNQSAEL IQPIATNGKV FPWAQIRLPT AIIPQRYELS
     LHPNLTSMTF RGSVTISLQA LQDTRDIILH STGHNISSVT FMSAVSSQEK QVEILEYPYH
     EQIAVVAPES LLTGHNYTLK IEYSANISNS YYGFYGITYT DKSNEKKNFA ATQFEPLAAR
     SAFPCFDEPA FKATFIIKIT RDEHHTALSN MPKKSSVPTE EGLIQDEFSE SVKMSTYLVA
     FIVGEMRNLS QDVNGTLVSV YAVPEKIDQV YHALDTTVKL LEFYQNYFEI QYPLKKLDLV
     AIPDFEAGAM ENWGLLTFRE ETLLYDNATS SVADRKLVTK IIAHELAHQW FGNLVTMQWW
     NDLWLNEGFA TFMEYFSVEK IFKELNSYED FLDARFKTMR KDSLNSSHPI SSSVQSSEQI
     EEMFDSLSYF KGASLLLMLK SYLSEDVFQH AIILYLHNHS YAAIQSDDLW DSFNEVTGKT
     LDVKKMMKTW TLQKGFPLVT VQRKGTELLL QQERFFPSMQ PEIQDSDTSH LWHIPISYVT
     DGRNYSEYRS VSLLDKKSDV INLTEQVQWV KVNTNMTGYY IVHYAHDGWA ALINQLKRNP
     YVLSDKDRAN LINNIFELAG LGKVPLQMAF DLIDYLRNET HTAPITEALF QTDLIYNLLE
     KLGHMDLSSR LVTRVHKLLQ NQIQQQTWTD EGTPSMRELR SALLEFACAH SLENCTTMAT
     KLFDGWMASN GTQSLPTDVM TTVFKVGART EKGWLFLFSM YSSMGSEAEK DKILEALASS
     ADAHKLYWLM KSSLDGDIIR TQKLSLIIRT VGRQFPGHLL AWDFVKENWN KLVHKFHLGS
     YTIQSIVAGS THLFSTKTHL SEVQEFFENQ SEATLQLRCV QEAFEVIELN IQWMARNLKT
     LTLWL
//