SEPR_HUMAN
ID SEPR_HUMAN Reviewed; 760 AA.
AC Q12884; O00199; Q53TP5; Q86Z29; Q99998; Q9UID4;
DT 05-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 23-MAR-2010, sequence version 5.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Prolyl endopeptidase FAP {ECO:0000305};
DE EC=3.4.21.26 {ECO:0000269|PubMed:16223769};
DE AltName: Full=170 kDa melanoma membrane-bound gelatinase {ECO:0000303|PubMed:2172980, ECO:0000303|PubMed:9065413};
DE AltName: Full=Dipeptidyl peptidase FAP {ECO:0000305};
DE EC=3.4.14.5 {ECO:0000269|PubMed:10347120};
DE AltName: Full=Fibroblast activation protein alpha {ECO:0000303|PubMed:7911242};
DE Short=FAPalpha {ECO:0000250|UniProtKB:P97321};
DE AltName: Full=Gelatine degradation protease FAP {ECO:0000305};
DE EC=3.4.21.- {ECO:0000269|PubMed:9065413};
DE AltName: Full=Integral membrane serine protease {ECO:0000303|PubMed:9247085};
DE AltName: Full=Post-proline cleaving enzyme {ECO:0000305};
DE AltName: Full=Serine integral membrane protease {ECO:0000303|PubMed:9247085};
DE Short=SIMP {ECO:0000303|PubMed:9247085};
DE AltName: Full=Surface-expressed protease {ECO:0000303|PubMed:2172980};
DE Short=Seprase {ECO:0000303|PubMed:7923219};
DE Contains:
DE RecName: Full=Antiplasmin-cleaving enzyme FAP, soluble form {ECO:0000303|PubMed:14751930};
DE Short=APCE {ECO:0000303|PubMed:14751930};
DE EC=3.4.14.5 {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769};
DE EC=3.4.21.- {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769};
DE EC=3.4.21.26 {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769};
GN Name=FAP {ECO:0000312|HGNC:HGNC:3590};
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), GLYCOSYLATION, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Fibroblast;
RX PubMed=7911242; DOI=10.1073/pnas.91.12.5657;
RA Scanlan M.J., Raj B.K.M., Calvo B., Garin-Chesa P., Sanz-Moncasi M.P.,
RA Healey J.H., Old L.J., Rettig W.J.;
RT "Molecular cloning of fibroblast activation protein alpha, a member of the
RT serine protease family selectively expressed in stromal fibroblasts of
RT epithelial cancers.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:5657-5661(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Melanoma;
RX PubMed=9247085; DOI=10.1016/s0925-4439(97)00032-x;
RA Goldstein L.A., Ghersi G., Pineiro-Sanchez M.L., Salamone M., Yeh Y.,
RA Flessate D., Chen W.-T.;
RT "Molecular cloning of seprase: a serine integral membrane protease from
RT human melanoma.";
RL Biochim. Biophys. Acta 1361:11-19(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 220-229;
RP 461-472 AND 511-518, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, ACTIVITY REGULATION, SUBUNIT, GLYCOSYLATION, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Melanoma;
RX PubMed=9065413; DOI=10.1074/jbc.272.12.7595;
RA Pineiro-Sanchez M.L., Goldstein L.A., Dodt J., Howard L., Yeh Y.,
RA Chen W.-T.;
RT "Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase)
RT as a serine integral membrane protease.";
RL J. Biol. Chem. 272:7595-7601(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Melanoma;
RX PubMed=10644713; DOI=10.1074/jbc.275.4.2554;
RA Goldstein L.A., Chen W.-T.;
RT "Identification of an alternatively spliced seprase mRNA that encodes a
RT novel intracellular isoform.";
RL J. Biol. Chem. 275:2554-2559(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [8]
RP PROTEIN SEQUENCE OF 24-38; 210-219; 247-254; 487-499; 500-509 AND 522-530,
RP FUNCTION (SOLUBLE FORM), CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=14751930; DOI=10.1182/blood-2003-12-4240;
RA Lee K.N., Jackson K.W., Christiansen V.J., Chung K.H., McKee P.A.;
RT "A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of
RT fibrin digestion.";
RL Blood 103:3783-3788(2004).
RN [9]
RP PROTEIN SEQUENCE OF 192-208; 220-240 AND 510-521, AND INDUCTION.
RX PubMed=7519584; DOI=10.1002/ijc.2910580314;
RA Rettig W.J., Su S.L., Fortunato S.R., Scanlan M.J., Raj B.K.M.,
RA Garin-Chesa P., Healey J.H., Old L.J.;
RT "Fibroblast activation protein: purification, epitope mapping and induction
RT by growth factors.";
RL Int. J. Cancer 58:385-392(1994).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=2172980; DOI=10.1073/pnas.87.21.8296;
RA Aoyama A., Chen W.T.;
RT "A 170-kDa membrane-bound protease is associated with the expression of
RT invasiveness by human malignant melanoma cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:8296-8300(1990).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=7923219;
RA Monsky W.L., Lin C.Y., Aoyama A., Kelly T., Akiyama S.K., Mueller S.C.,
RA Chen W.T.;
RT "A potential marker protease of invasiveness, seprase, is localized on
RT invadopodia of human malignant melanoma cells.";
RL Cancer Res. 54:5702-5710(1994).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=10347120; DOI=10.1002/hep.510290631;
RA Levy M.T., McCaughan G.W., Abbott C.A., Park J.E., Cunningham A.M.,
RA Mueller E., Rettig W.J., Gorrell M.D.;
RT "Fibroblast activation protein: a cell surface dipeptidyl peptidase and
RT gelatinase expressed by stellate cells at the tissue remodelling interface
RT in human cirrhosis.";
RL Hepatology 29:1768-1778(1999).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF
RP SER-624.
RX PubMed=10593948; DOI=10.1074/jbc.274.51.36505;
RA Park J.E., Lenter M.C., Zimmermann R.N., Garin-Chesa P., Old L.J.,
RA Rettig W.J.;
RT "Fibroblast activation protein, a dual specificity serine protease
RT expressed in reactive human tumor stromal fibroblasts.";
RL J. Biol. Chem. 274:36505-36512(1999).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, INTERACTION WITH ITGA3 AND ITGB1,
RP ASSOCIATION WITH INTEGRIN ALPHA-3/BETA-1, AND SUBCELLULAR LOCATION.
RX PubMed=10455171; DOI=10.1074/jbc.274.35.24947;
RA Mueller S.C., Ghersi G., Akiyama S.K., Sang Q.X., Howard L.,
RA Pineiro-Sanchez M., Nakahara H., Yeh Y., Chen W.T.;
RT "A novel protease-docking function of integrin at invadopodia.";
RL J. Biol. Chem. 274:24947-24952(1999).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PLAUR, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12376466; DOI=10.1093/carcin/23.10.1593;
RA Artym V.V., Kindzelskii A.L., Chen W.T., Petty H.R.;
RT "Molecular proximity of seprase and the urokinase-type plasminogen
RT activator receptor on malignant melanoma cell membranes: dependence on
RT beta1 integrins and the cytoskeleton.";
RL Carcinogenesis 23:1593-1601(2002).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF GLU-203; GLU-204 AND SER-624.
RX PubMed=16175601; DOI=10.1002/hep.20853;
RA Wang X.M., Yu D.M., McCaughan G.W., Gorrell M.D.;
RT "Fibroblast activation protein increases apoptosis, cell adhesion, and
RT migration by the LX-2 human stellate cell line.";
RL Hepatology 42:935-945(2005).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-99 AND ASN-227.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17105646; DOI=10.1186/ar2080;
RA Bauer S., Jendro M.C., Wadle A., Kleber S., Stenner F., Dinser R.,
RA Reich A., Faccin E., Goedde S., Dinges H., Mueller-Ladner U., Renner C.;
RT "Fibroblast activation protein is expressed by rheumatoid myofibroblast-
RT like synoviocytes.";
RL Arthritis Res. Ther. 8:R171-R171(2006).
RN [19]
RP FUNCTION (PLASMA MEMBRANE AND SOLUBLE FORMS), CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=16223769; DOI=10.1182/blood-2005-08-3452;
RA Lee K.N., Jackson K.W., Christiansen V.J., Lee C.S., Chun J.G., McKee P.A.;
RT "Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation
RT protein.";
RL Blood 107:1397-1404(2006).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, HETERODIMERIZATION WITH DPP4, AND SUBCELLULAR
RP LOCATION.
RX PubMed=16651416; DOI=10.1158/0008-5472.can-05-1245;
RA Ghersi G., Zhao Q., Salamone M., Yeh Y., Zucker S., Chen W.T.;
RT "The protease complex consisting of dipeptidyl peptidase IV and seprase
RT plays a role in the migration and invasion of human endothelial cells in
RT collagenous matrices.";
RL Cancer Res. 66:4652-4661(2006).
RN [21]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=16480718; DOI=10.1016/j.febslet.2006.01.087;
RA Edosada C.Y., Quan C., Tran T., Pham V., Wiesmann C., Fairbrother W.,
RA Wolf B.B.;
RT "Peptide substrate profiling defines fibroblast activation protein as an
RT endopeptidase of strict Gly(2)-Pro(1)-cleaving specificity.";
RL FEBS Lett. 580:1581-1586(2006).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, AND SUBUNIT.
RX PubMed=16410248; DOI=10.1074/jbc.m511112200;
RA Edosada C.Y., Quan C., Wiesmann C., Tran T., Sutherlin D., Reynolds M.,
RA Elliott J.M., Raab H., Fairbrother W., Wolf B.B.;
RT "Selective inhibition of fibroblast activation protein protease based on
RT dipeptide substrate specificity.";
RL J. Biol. Chem. 281:7437-7444(2006).
RN [23]
RP FUNCTION, MUTAGENESIS OF ARG-123; GLU-203; TYR-656; ALA-657 AND ASN-704,
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION.
RX PubMed=17381073; DOI=10.1021/bi062227y;
RA Meadows S.A., Edosada C.Y., Mayeda M., Tran T., Quan C., Raab H.,
RA Wiesmann C., Wolf B.B.;
RT "Ala657 and conserved active site residues promote fibroblast activation
RT protein endopeptidase activity via distinct mechanisms of transition state
RT stabilization.";
RL Biochemistry 46:4598-4605(2007).
RN [24]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=18095711; DOI=10.1021/bi701921b;
RA Aggarwal S., Brennen W.N., Kole T.P., Schneider E., Topaloglu O., Yates M.,
RA Cotter R.J., Denmeade S.R.;
RT "Fibroblast activation protein peptide substrates identified from human
RT collagen I derived gelatin cleavage sites.";
RL Biochemistry 47:1076-1086(2008).
RN [25]
RP REVIEW, AND FUNCTION.
RX PubMed=18262497; DOI=10.1016/j.bbapap.2008.01.006;
RA O'Brien P., O'Connor B.F.;
RT "Seprase: an overview of an important matrix serine protease.";
RL Biochim. Biophys. Acta 1784:1130-1145(2008).
RN [26]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=20707604; DOI=10.1515/bc.2010.119;
RA Mentlein R., Hattermann K., Hemion C., Jungbluth A.A., Held-Feindt J.;
RT "Expression and role of the cell surface protease seprase/fibroblast
RT activation protein-alpha (FAP-alpha) in astroglial tumors.";
RL Biol. Chem. 392:199-207(2011).
RN [27]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21314817; DOI=10.1111/j.1742-4658.2011.08051.x;
RA Keane F.M., Nadvi N.A., Yao T.W., Gorrell M.D.;
RT "Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are
RT novel substrates of fibroblast activation protein-alpha.";
RL FEBS J. 278:1316-1332(2011).
RN [28]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21288888; DOI=10.1093/jb/mvr017;
RA Huang C.H., Suen C.S., Lin C.T., Chien C.H., Lee H.Y., Chung K.M.,
RA Tsai T.Y., Jiaang W.T., Hwang M.J., Chen X.;
RT "Cleavage-site specificity of prolyl endopeptidase FAP investigated with a
RT full-length protein substrate.";
RL J. Biochem. 149:685-692(2011).
RN [29]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP CHARACTERIZATION OF VARIANT LEU-363.
RX PubMed=24371721; DOI=10.1016/j.fob.2013.12.001;
RA Keane F.M., Yao T.W., Seelk S., Gall M.G., Chowdhury S., Poplawski S.E.,
RA Lai J.H., Li Y., Wu W., Farrell P., Vieira de Ribeiro A.J., Osborne B.,
RA Yu D.M., Seth D., Rahman K., Haber P., Topaloglu A.K., Wang C., Thomson S.,
RA Hennessy A., Prins J., Twigg S.M., McLennan S.V., McCaughan G.W.,
RA Bachovchin W.W., Gorrell M.D.;
RT "Quantitation of fibroblast activation protein (FAP)-specific protease
RT activity in mouse, baboon and human fluids and organs.";
RL FEBS Open Bio 4:43-54(2013).
RN [30]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF
RP VARIANT LEU-363.
RX PubMed=24717288; DOI=10.1016/j.bbapap.2014.03.015;
RA Osborne B., Yao T.W., Wang X.M., Chen Y., Kotan L.D., Nadvi N.A.,
RA Herdem M., McCaughan G.W., Allen J.D., Yu D.M., Topaloglu A.K.,
RA Gorrell M.D.;
RT "A rare variant in human fibroblast activation protein associated with ER
RT stress, loss of enzymatic function and loss of cell surface localisation.";
RL Biochim. Biophys. Acta 1844:1248-1259(2014).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 39-757, SUBSTRATE BINDING,
RP SUBUNIT, DISULFIDE BONDS, ACTIVE SITE, AND GLYCOSYLATION AT ASN-49; ASN-92;
RP ASN-227 AND ASN-314.
RX PubMed=15809306; DOI=10.1074/jbc.c500092200;
RA Aertgeerts K., Levin I., Shi L., Snell G.P., Jennings A., Prasad G.S.,
RA Zhang Y., Kraus M.L., Salakian S., Sridhar V., Wijnands R., Tennant M.G.;
RT "Structural and kinetic analysis of the substrate specificity of human
RT fibroblast activation protein alpha.";
RL J. Biol. Chem. 280:19441-19444(2005).
CC -!- FUNCTION: Cell surface glycoprotein serine protease that participates
CC in extracellular matrix degradation and involved in many cellular
CC processes including tissue remodeling, fibrosis, wound healing,
CC inflammation and tumor growth. Both plasma membrane and soluble forms
CC exhibit post-proline cleaving endopeptidase activity, with a marked
CC preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on
CC substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2
CC (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248,
CC PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721).
CC Degrade also gelatin, heat-denatured type I collagen, but not native
CC collagen type I and IV, vitronectin, tenascin, laminin, fibronectin,
CC fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219,
CC PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769,
CC PubMed:16651416, PubMed:18095711). Also has dipeptidyl peptidase
CC activity, exhibiting the ability to hydrolyze the prolyl bond two
CC residues from the N-terminus of synthetic dipeptide substrates provided
CC that the penultimate residue is proline, with a preference for Ala-Pro,
CC Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120,
CC PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416,
CC PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721,
CC PubMed:24717288). Natural neuropeptide hormones for dipeptidyl
CC peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P
CC (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The
CC plasma membrane form, in association with either DPP4, PLAUR or
CC integrins, is involved in the pericellular proteolysis of the
CC extracellular matrix (ECM), and hence promotes cell adhesion, migration
CC and invasion through the ECM. Plays a role in tissue remodeling during
CC development and wound healing. Participates in the cell invasiveness
CC towards the ECM in malignant melanoma cancers. Enhances tumor growth
CC progression by increasing angiogenesis, collagen fiber degradation and
CC apoptosis and by reducing antitumor response of the immune system.
CC Promotes glioma cell invasion through the brain parenchyma by degrading
CC the proteoglycan brevican. Acts as a tumor suppressor in melanocytic
CC cells through regulation of cell proliferation and survival in a serine
CC protease activity-independent manner. {ECO:0000250|UniProtKB:P97321,
CC ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10455171,
CC ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:12376466,
CC ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16175601,
CC ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248,
CC ECO:0000269|PubMed:16480718, ECO:0000269|PubMed:16651416,
CC ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:17381073,
CC ECO:0000269|PubMed:18095711, ECO:0000269|PubMed:20707604,
CC ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:21314817,
CC ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24371721,
CC ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7923219,
CC ECO:0000269|PubMed:9065413}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides.;
CC EC=3.4.21.26; Evidence={ECO:0000269|PubMed:14751930,
CC ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248,
CC ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:18095711,
CC ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:24371721};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a
CC polypeptide, preferentially when Yaa is Pro, provided Zaa is neither
CC Pro nor hydroxyproline.; EC=3.4.14.5; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU10084, ECO:0000269|PubMed:10347120,
CC ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:16175601,
CC ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248,
CC ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17381073,
CC ECO:0000269|PubMed:21314817, ECO:0000269|PubMed:24371721,
CC ECO:0000269|PubMed:24717288};
CC -!- ACTIVITY REGULATION: Gelatinase activity is inhibited by serine-
CC protease inhibitors, such as phenylmethylsulfonyl fluoride (PMSF), 4-
CC (2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF), 4-
CC amidino phenylsulfonyl fluoride (APSF) and diisopropyl fluorophosphate
CC (DFP), N-ethylmaleimide (NEM) and phenylmethylsulfonyl fluoride (PMSF).
CC Dipeptidyl peptidase activity is inhibited by 2,2'-azino-bis(3-
CC ethylbenzthiazoline-6-sulfonic acid), diisopropylfluorophosphate (DFP).
CC Prolyl endopeptidase activity is inhibited by the boronic acid peptide
CC Ac-Gly-BoroPro, Ac-Gly-Pro-chloromethyl ketone and Thr-Ser-Gly-
CC chloromethyl ketone. {ECO:0000269|PubMed:10593948,
CC ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16480718,
CC ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:2172980,
CC ECO:0000269|PubMed:9065413}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.46 mM for Ala-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:10593948};
CC KM=0.9 mM for Lys-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:10593948};
CC KM=1.15 mM for Gly-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:10593948};
CC KM=0.25 mM for Gly-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:17381073};
CC KM=0.24 mM for Ala-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:16410248};
CC KM=0.10 mM for Ile-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:16410248};
CC KM=0.24 mM for Phe-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:16410248};
CC KM=0.24 mM for Gly-Pro (Dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:16410248};
CC KM=0.33 mM for Ac-Gly-Pro (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:17381073};
CC KM=1.3 uM for Thr-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=2.2 uM for Ala-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=0.7 uM for Thr-Ala-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=1.9 uM for Thr-Ser-Gly-Pro-Ser-Gln (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=2.2 uM for Thr-Ser-Gly-Pro-Asn-Ser (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=4.3 uM for Ala-Ser-Gly-Pro-Ser-Ser (Prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16480718};
CC KM=0.101 mM for Gly-Pro (FAP form, prolyl endopeptidase activity)
CC {ECO:0000269|PubMed:16223769};
CC KM=0.124 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble
CC form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769};
CC KM=0.323 mM for Gly-Pro (FAP form, dipeptidyl peptidase activity)
CC {ECO:0000269|PubMed:16223769};
CC KM=0.272 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble
CC form, dipeptidyl peptidase activity) {ECO:0000269|PubMed:16223769};
CC KM=0.029 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu (FAP
CC form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769};
CC KM=0.026 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu
CC (Antiplasmin-cleaving enzyme FAP soluble form, prolyl endopeptidase
CC activity) {ECO:0000269|PubMed:16223769};
CC pH dependence:
CC Optimum pH is 6-8.4 for gelatinase activity. At pH lower than 5
CC inhibited gelatinase activity. {ECO:0000269|PubMed:2172980,
CC ECO:0000269|PubMed:9065413};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius for gelatinase activity.
CC Temperatures above 50 degrees Celsius inhibit gelatinase activity.
CC {ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:9065413};
CC -!- SUBUNIT: Homodimer; homodimerization is required for activity of both
CC plasma membrane and soluble forms. The monomer is inactive. Heterodimer
CC with DPP4. Interacts with PLAUR; the interaction occurs at the cell
CC surface of invadopodia membranes. Interacts with ITGB1. Interacts with
CC ITGA3. Associates with integrin alpha-3/beta-1; the association occurs
CC in a collagen-dependent manner at the cell surface of invadopodia
CC membranes. {ECO:0000269|PubMed:10455171, ECO:0000269|PubMed:12376466,
CC ECO:0000269|PubMed:15809306, ECO:0000269|PubMed:16223769,
CC ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16651416,
CC ECO:0000269|PubMed:9065413}.
CC -!- INTERACTION:
CC Q12884; P01275: GCG; NbExp=4; IntAct=EBI-4319803, EBI-7629173;
CC Q12884; P01282: VIP; NbExp=2; IntAct=EBI-4319803, EBI-751454;
CC -!- SUBCELLULAR LOCATION: [Prolyl endopeptidase FAP]: Cell surface
CC {ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:16175601,
CC ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:24717288,
CC ECO:0000269|PubMed:7911242}. Cell membrane
CC {ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:16651416,
CC ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}; Single-pass
CC type II membrane protein {ECO:0000255}. Cell projection, lamellipodium
CC membrane {ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:9065413};
CC Single-pass type II membrane protein {ECO:0000255}. Cell projection,
CC invadopodium membrane {ECO:0000269|PubMed:12376466,
CC ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:7923219,
CC ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}; Single-pass
CC type II membrane protein {ECO:0000255}. Cell projection, ruffle
CC membrane {ECO:0000303|PubMed:10455171}; Single-pass type II membrane
CC protein {ECO:0000255}. Membrane {ECO:0000269|PubMed:2172980}; Single-
CC pass type II membrane protein {ECO:0000255}. Note=Localized on cell
CC surface with lamellipodia and invadopodia membranes and on shed
CC vesicles. Colocalized with DPP4 at invadopodia and lamellipodia
CC membranes of migratory activated endothelial cells in collagenous
CC matrix. Colocalized with DPP4 on endothelial cells of capillary-like
CC microvessels but not large vessels within invasive breast ductal
CC carcinoma. Anchored and enriched preferentially by integrin alpha-
CC 3/beta-1 at invadopodia, plasma membrane protrusions that correspond to
CC sites of cell invasion, in a collagen-dependent manner. Localized at
CC plasma and ruffle membranes in a collagen-independent manner.
CC Colocalized with PLAUR preferentially at the cell surface of
CC invadopodia membranes in a cytoskeleton-, integrin- and vitronectin-
CC dependent manner. Concentrated at invadopodia membranes, specialized
CC protrusions of the ventral plasma membrane in a fibrobectin-dependent
CC manner. Colocalizes with extracellular components (ECM), such as
CC collagen fibers and fibronectin. {ECO:0000269|PubMed:10593948,
CC ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:16175601,
CC ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17105646,
CC ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24717288,
CC ECO:0000269|PubMed:7911242, ECO:0000269|PubMed:7923219,
CC ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}.
CC -!- SUBCELLULAR LOCATION: [Antiplasmin-cleaving enzyme FAP, soluble form]:
CC Secreted {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769,
CC ECO:0000269|PubMed:24371721}. Note=Found in blood plasma and serum.
CC {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769,
CC ECO:0000269|PubMed:24371721}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000303|PubMed:10644713}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=L, seprase-I {ECO:0000303|PubMed:10644713};
CC IsoId=Q12884-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:10644713}; Synonyms=S, Truncated, seprase-s
CC {ECO:0000303|PubMed:10644713};
CC IsoId=Q12884-2; Sequence=VSP_005367;
CC -!- TISSUE SPECIFICITY: Expressed in adipose tissue. Expressed in the
CC dermal fibroblasts in the fetal skin. Expressed in the granulation
CC tissue of healing wounds and on reactive stromal fibroblast in
CC epithelial cancers. Expressed in activated fibroblast-like synoviocytes
CC from inflamed synovial tissues. Expressed in activated hepatic stellate
CC cells (HSC) and myofibroblasts from cirrhotic liver, but not detected
CC in normal liver. Expressed in glioma cells (at protein level).
CC Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2
CC are expressed in melanoma, carcinoma and fibroblast cell lines.
CC {ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10593948,
CC ECO:0000269|PubMed:10644713, ECO:0000269|PubMed:16175601,
CC ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:20707604,
CC ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:7911242}.
CC -!- INDUCTION: In fibroblasts at times and sites of tissue remodeling
CC during development, tissue repair and carcinogenesis. Up-regulated upon
CC tumor stem cell differentiation. Up-regulated by transforming growth
CC factor-beta, 12-O-tetradecanoyl phorbol-13-acetate and retinoids.
CC {ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:7519584}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:15809306,
CC ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:7911242,
CC ECO:0000269|PubMed:9065413}.
CC -!- PTM: The N-terminus may be blocked.
CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform.
CC -!- MISCELLANEOUS: [Isoform 2]: Upstream open reading frames ORF(s)-
CC containing region inhibits the translation of its downstream ORF.
CC {ECO:0000269|PubMed:10644713}.
CC -!- SIMILARITY: Belongs to the peptidase S9B family. {ECO:0000305}.
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DR EMBL; U09278; AAB49652.1; -; mRNA.
DR EMBL; U76833; AAC51668.1; -; mRNA.
DR EMBL; AF007822; AAF21600.1; -; mRNA.
DR EMBL; AC007750; AAY24205.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11353.1; -; Genomic_DNA.
DR EMBL; BC026250; AAH26250.1; -; mRNA.
DR CCDS; CCDS33311.1; -. [Q12884-1]
DR RefSeq; NP_001278736.1; NM_001291807.2.
DR RefSeq; NP_004451.2; NM_004460.4. [Q12884-1]
DR PDB; 1Z68; X-ray; 2.60 A; A/B=39-757.
DR PDB; 6Y0F; X-ray; 2.92 A; A/B/C/D=36-757.
DR PDBsum; 1Z68; -.
DR PDBsum; 6Y0F; -.
DR AlphaFoldDB; Q12884; -.
DR SMR; Q12884; -.
DR BioGRID; 108485; 18.
DR IntAct; Q12884; 10.
DR MINT; Q12884; -.
DR STRING; 9606.ENSP00000188790; -.
DR BindingDB; Q12884; -.
DR ChEMBL; CHEMBL4683; -.
DR DrugBank; DB06474; Sibrotuzumab.
DR DrugCentral; Q12884; -.
DR GuidetoPHARMACOLOGY; 2365; -.
DR ESTHER; human-FAP; DPP4N_Peptidase_S9.
DR MEROPS; S09.007; -.
DR GlyConnect; 1641; 12 N-Linked glycans (3 sites).
DR GlyGen; Q12884; 6 sites, 12 N-linked glycans (3 sites).
DR iPTMnet; Q12884; -.
DR PhosphoSitePlus; Q12884; -.
DR SwissPalm; Q12884; -.
DR BioMuta; FAP; -.
DR DMDM; 292495099; -.
DR EPD; Q12884; -.
DR jPOST; Q12884; -.
DR MassIVE; Q12884; -.
DR PaxDb; Q12884; -.
DR PeptideAtlas; Q12884; -.
DR PRIDE; Q12884; -.
DR ProteomicsDB; 59000; -. [Q12884-1]
DR ProteomicsDB; 59001; -. [Q12884-2]
DR ABCD; Q12884; 31 sequenced antibodies.
DR Antibodypedia; 33750; 628 antibodies from 42 providers.
DR DNASU; 2191; -.
DR Ensembl; ENST00000188790.9; ENSP00000188790.4; ENSG00000078098.15. [Q12884-1]
DR GeneID; 2191; -.
DR KEGG; hsa:2191; -.
DR MANE-Select; ENST00000188790.9; ENSP00000188790.4; NM_004460.5; NP_004451.2.
DR UCSC; uc002ucd.3; human. [Q12884-1]
DR CTD; 2191; -.
DR DisGeNET; 2191; -.
DR GeneCards; FAP; -.
DR HGNC; HGNC:3590; FAP.
DR HPA; ENSG00000078098; Tissue enhanced (endometrium, smooth muscle).
DR MIM; 600403; gene.
DR neXtProt; NX_Q12884; -.
DR OpenTargets; ENSG00000078098; -.
DR PharmGKB; PA28003; -.
DR VEuPathDB; HostDB:ENSG00000078098; -.
DR eggNOG; KOG2100; Eukaryota.
DR GeneTree; ENSGT00940000160454; -.
DR InParanoid; Q12884; -.
DR OMA; MRTPQEN; -.
DR OrthoDB; 269253at2759; -.
DR PhylomeDB; Q12884; -.
DR TreeFam; TF313309; -.
DR BRENDA; 3.4.21.B28; 2681.
DR PathwayCommons; Q12884; -.
DR SABIO-RK; Q12884; -.
DR SignaLink; Q12884; -.
DR SIGNOR; Q12884; -.
DR BioGRID-ORCS; 2191; 10 hits in 1067 CRISPR screens.
DR ChiTaRS; FAP; human.
DR EvolutionaryTrace; Q12884; -.
DR GeneWiki; Fibroblast_activation_protein,_alpha; -.
DR GenomeRNAi; 2191; -.
DR Pharos; Q12884; Tchem.
DR PRO; PR:Q12884; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q12884; protein.
DR Bgee; ENSG00000078098; Expressed in stromal cell of endometrium and 122 other tissues.
DR ExpressionAtlas; Q12884; baseline and differential.
DR Genevisible; Q12884; HS.
DR GO; GO:0045177; C:apical part of cell; IEA:Ensembl.
DR GO; GO:0045178; C:basal part of cell; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0030027; C:lamellipodium; IDA:UniProtKB.
DR GO; GO:0031258; C:lamellipodium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1905368; C:peptidase complex; IMP:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; NAS:UniProtKB.
DR GO; GO:0008239; F:dipeptidyl-peptidase activity; IDA:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0005178; F:integrin binding; IPI:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0002020; F:protease binding; IPI:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0043542; P:endothelial cell migration; IDA:UniProtKB.
DR GO; GO:1902362; P:melanocyte apoptotic process; ISS:UniProtKB.
DR GO; GO:0097325; P:melanocyte proliferation; ISS:UniProtKB.
DR GO; GO:0060244; P:negative regulation of cell proliferation involved in contact inhibition; ISS:UniProtKB.
DR GO; GO:0010716; P:negative regulation of extracellular matrix disassembly; IDA:UniProtKB.
DR GO; GO:1903054; P:negative regulation of extracellular matrix organization; IDA:UniProtKB.
DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; IDA:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; ISS:UniProtKB.
DR GO; GO:0010710; P:regulation of collagen catabolic process; IDA:UniProtKB.
DR GO; GO:0051917; P:regulation of fibrinolysis; IC:BHF-UCL.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR031245; FAP-alpha.
DR InterPro; IPR002471; Pept_S9_AS.
DR InterPro; IPR001375; Peptidase_S9.
DR InterPro; IPR002469; Peptidase_S9B_N.
DR PANTHER; PTHR11731:SF136; PTHR11731:SF136; 1.
DR Pfam; PF00930; DPPIV_N; 1.
DR Pfam; PF00326; Peptidase_S9; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Apoptosis; Cell adhesion;
KW Cell junction; Cell membrane; Cell projection;
KW Cleavage on pair of basic residues; Cytoplasm; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Hydrolase; Membrane; Protease;
KW Reference proteome; Secreted; Serine protease; Signal-anchor;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..760
FT /note="Prolyl endopeptidase FAP"
FT /evidence="ECO:0000305"
FT /id="PRO_0000122424"
FT CHAIN 24..760
FT /note="Antiplasmin-cleaving enzyme FAP, soluble form"
FT /evidence="ECO:0000303|PubMed:14751930"
FT /id="PRO_0000430643"
FT TOPO_DOM 1..4
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255, ECO:0000303|PubMed:14751930"
FT TRANSMEM 5..25
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 26..760
FT /note="Extracellular"
FT /evidence="ECO:0000255, ECO:0000303|PubMed:14751930"
FT ACT_SITE 624
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10084,
FT ECO:0000269|PubMed:15809306"
FT ACT_SITE 702
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:15809306"
FT ACT_SITE 734
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:15809306"
FT BINDING 203
FT /ligand="substrate"
FT /evidence="ECO:0000303|PubMed:15809306"
FT BINDING 204
FT /ligand="substrate"
FT /evidence="ECO:0000303|PubMed:15809306"
FT SITE 23..24
FT /note="Cleavage"
FT /evidence="ECO:0000303|PubMed:14751930"
FT CARBOHYD 49
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498,
FT ECO:0000269|PubMed:15809306"
FT CARBOHYD 92
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498,
FT ECO:0000269|PubMed:15809306"
FT CARBOHYD 99
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498,
FT ECO:0000269|PubMed:16335952"
FT CARBOHYD 227
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498,
FT ECO:0000269|PubMed:15809306, ECO:0000269|PubMed:16335952"
FT CARBOHYD 314
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498,
FT ECO:0000269|PubMed:15809306"
FT CARBOHYD 679
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 321..332
FT /evidence="ECO:0000269|PubMed:15809306"
FT DISULFID 438..441
FT /evidence="ECO:0000269|PubMed:15809306"
FT DISULFID 448..466
FT /evidence="ECO:0000269|PubMed:15809306"
FT DISULFID 643..755
FT /evidence="ECO:0000269|PubMed:15809306"
FT VAR_SEQ 1..521
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10644713"
FT /id="VSP_005367"
FT VARIANT 363
FT /note="S -> L (decreased plasma membrane expression; loss
FT of homodimerization and dipeptidyl peptidase activity;
FT mislocalized with the calnexin in the endoplasmic
FT reticulum; causes induction of the unfolded protein
FT response (UPR); dbSNP:rs762738740)"
FT /evidence="ECO:0000269|PubMed:24371721,
FT ECO:0000269|PubMed:24717288"
FT /id="VAR_071264"
FT MUTAGEN 123
FT /note="R->A,M,E: Reduces dipeptidyl peptidase and
FT endopeptidase activities."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 203
FT /note="E->A,D,Q: Reduces dipeptidyl peptidase and
FT endopeptidase activities. Does not inhibit cell adhesion,
FT migration and invasion. Inhibits dipeptidyl peptidase and
FT endopeptidase activities; when associated with A-204."
FT /evidence="ECO:0000269|PubMed:16175601,
FT ECO:0000269|PubMed:17381073"
FT MUTAGEN 204
FT /note="E->A,D,Q: Reduces dipeptidyl peptidase and
FT endopeptidase activities. Does not inhibit cell adhesion,
FT migration and invasion. Inhibits dipeptidyl peptidase and
FT endopeptidase activities; when associated with A-203."
FT /evidence="ECO:0000269|PubMed:16175601,
FT ECO:0000269|PubMed:17381073"
FT MUTAGEN 624
FT /note="S->A: Reduces dipeptidyl peptidase and gelatinolytic
FT activities. Does not inhibit cell adhesion, migration and
FT invasion."
FT /evidence="ECO:0000269|PubMed:10593948,
FT ECO:0000269|PubMed:16175601"
FT MUTAGEN 656
FT /note="Y->F: Reduces dipeptidyl peptidase and endopeptidase
FT activities."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 657
FT /note="A->D,N: Inhibits endopeptidase activity. Increases
FT dipeptidyl peptidase activity."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 657
FT /note="A->F,V: Reduces dipeptidyl peptidase and
FT endopeptidase activities."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 657
FT /note="A->Q: Inhibits endopeptidase activity. No change in
FT dipeptidyl peptidase activity."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 657
FT /note="A->S,T: Reduces strongly endopeptidase activity. No
FT change in dipeptidyl peptidase activity."
FT /evidence="ECO:0000269|PubMed:17381073"
FT MUTAGEN 704
FT /note="N->A: Reduces dipeptidyl peptidase and endopeptidase
FT activities."
FT /evidence="ECO:0000269|PubMed:17381073"
FT CONFLICT 207
FT /note="A -> P (in Ref. 1; AAB49652)"
FT /evidence="ECO:0000305"
FT CONFLICT 229
FT /note="T -> K (in Ref. 1; AAB49652)"
FT /evidence="ECO:0000305"
FT CONFLICT 354
FT /note="T -> R (in Ref. 1; AAB49652)"
FT /evidence="ECO:0000305"
FT HELIX 44..49
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 50..52
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 60..70
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 76..83
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 86..90
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 92..96
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 97..99
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 101..105
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 109..120
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 126..134
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 135..138
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 157..160
FT /evidence="ECO:0007829|PDB:6Y0F"
FT STRAND 162..166
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 169..175
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 189..191
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 192..196
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 199..204
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 212..214
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 218..227
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 233..238
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 241..244
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 246..251
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 261..270
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 272..275
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 284..287
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 291..312
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 315..323
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 325..331
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 337..341
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 343..345
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 347..351
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 364..369
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 375..382
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 393..395
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 397..403
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 405..413
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 415..417
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 422..428
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 430..433
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 436..440
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 441..447
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 450..455
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 457..459
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 460..466
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 469..471
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 473..477
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 479..481
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 484..489
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 492..497
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 498..500
FT /evidence="ECO:0007829|PDB:6Y0F"
FT STRAND 505..513
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 516..524
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 530..532
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 534..540
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 557..563
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 568..573
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 577..580
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 582..585
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 586..588
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 594..608
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 609..612
FT /evidence="ECO:0007829|PDB:6Y0F"
FT STRAND 613..623
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 625..634
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 637..639
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 642..648
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 653..655
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 658..665
FT /evidence="ECO:0007829|PDB:1Z68"
FT TURN 670..673
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 674..679
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 683..689
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 692..699
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 703..705
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 708..719
FT /evidence="ECO:0007829|PDB:1Z68"
FT STRAND 725..729
FT /evidence="ECO:0007829|PDB:1Z68"
FT HELIX 739..756
FT /evidence="ECO:0007829|PDB:1Z68"
SQ SEQUENCE 760 AA; 87713 MW; 7FF817B5A4F75142 CRC64;
MKTWVKIVFG VATSAVLALL VMCIVLRPSR VHNSEENTMR ALTLKDILNG TFSYKTFFPN
WISGQEYLHQ SADNNIVLYN IETGQSYTIL SNRTMKSVNA SNYGLSPDRQ FVYLESDYSK
LWRYSYTATY YIYDLSNGEF VRGNELPRPI QYLCWSPVGS KLAYVYQNNI YLKQRPGDPP
FQITFNGREN KIFNGIPDWV YEEEMLATKY ALWWSPNGKF LAYAEFNDTD IPVIAYSYYG
DEQYPRTINI PYPKAGAKNP VVRIFIIDTT YPAYVGPQEV PVPAMIASSD YYFSWLTWVT
DERVCLQWLK RVQNVSVLSI CDFREDWQTW DCPKTQEHIE ESRTGWAGGF FVSTPVFSYD
AISYYKIFSD KDGYKHIHYI KDTVENAIQI TSGKWEAINI FRVTQDSLFY SSNEFEEYPG
RRNIYRISIG SYPPSKKCVT CHLRKERCQY YTASFSDYAK YYALVCYGPG IPISTLHDGR
TDQEIKILEE NKELENALKN IQLPKEEIKK LEVDEITLWY KMILPPQFDR SKKYPLLIQV
YGGPCSQSVR SVFAVNWISY LASKEGMVIA LVDGRGTAFQ GDKLLYAVYR KLGVYEVEDQ
ITAVRKFIEM GFIDEKRIAI WGWSYGGYVS SLALASGTGL FKCGIAVAPV SSWEYYASVY
TERFMGLPTK DDNLEHYKNS TVMARAEYFR NVDYLLIHGT ADDNVHFQNS AQIAKALVNA
QVDFQAMWYS DQNHGLSGLS TNHLYTHMTH FLKQCFSLSD
