| IED ID | IndEnz0002010563 |
| Enzyme Type ID | protease010563 |
| Protein Name |
Prolyl endopeptidase FAP EC 3.4.21.26 170 kDa melanoma membrane-bound gelatinase Dipeptidyl peptidase FAP EC 3.4.14.5 Fibroblast activation protein alpha FAPalpha Gelatine degradation protease FAP EC 3.4.21.- Integral membrane serine protease Post-proline cleaving enzyme Serine integral membrane protease SIMP Surface-expressed protease Seprase Cleaved into: Antiplasmin-cleaving enzyme FAP, soluble form APCE EC 3.4.14.5 EC 3.4.21.- EC 3.4.21.26 |
| Gene Name | FAP |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSKLWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYGDEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVTDERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGRTDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVYTERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD |
| Enzyme Length | 760 |
| Uniprot Accession Number | Q12884 |
| Absorption | |
| Active Site | ACT_SITE 624; /note="Charge relay system"; /evidence="ECO:0000255|PROSITE-ProRule:PRU10084, ECO:0000269|PubMed:15809306"; ACT_SITE 702; /note="Charge relay system"; /evidence="ECO:0000269|PubMed:15809306"; ACT_SITE 734; /note="Charge relay system"; /evidence="ECO:0000269|PubMed:15809306" |
| Activity Regulation | ACTIVITY REGULATION: Gelatinase activity is inhibited by serine-protease inhibitors, such as phenylmethylsulfonyl fluoride (PMSF), 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF), 4-amidino phenylsulfonyl fluoride (APSF) and diisopropyl fluorophosphate (DFP), N-ethylmaleimide (NEM) and phenylmethylsulfonyl fluoride (PMSF). Dipeptidyl peptidase activity is inhibited by 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), diisopropylfluorophosphate (DFP). Prolyl endopeptidase activity is inhibited by the boronic acid peptide Ac-Gly-BoroPro, Ac-Gly-Pro-chloromethyl ketone and Thr-Ser-Gly-chloromethyl ketone. {ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16480718, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:9065413}. |
| Binding Site | BINDING 203; /note=Substrate; /evidence=ECO:0000303|PubMed:15809306; BINDING 204; /note=Substrate; /evidence=ECO:0000303|PubMed:15809306 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides.; EC=3.4.21.26; Evidence={ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:18095711, ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:24371721}; CATALYTIC ACTIVITY: Reaction=Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline.; EC=3.4.14.5; Evidence={ECO:0000255|PROSITE-ProRule:PRU10084, ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:21314817, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:24717288}; |
| DNA Binding | |
| EC Number | 3.4.21.26; 3.4.14.5; 3.4.21.-; 3.4.14.5; 3.4.21.-; 3.4.21.26 |
| Enzyme Function | FUNCTION: Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2 (PubMed:14751930, PubMed:16223769, PubMed:16480718, PubMed:16410248, PubMed:17381073, PubMed:18095711, PubMed:21288888, PubMed:24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). Also has dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro (PubMed:10347120, PubMed:10593948, PubMed:16175601, PubMed:16223769, PubMed:16651416, PubMed:16410248, PubMed:17381073, PubMed:21314817, PubMed:24371721, PubMed:24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed:21314817). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner. {ECO:0000250|UniProtKB:P97321, ECO:0000269|PubMed:10347120, ECO:0000269|PubMed:10455171, ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:16480718, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:17381073, ECO:0000269|PubMed:18095711, ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:21288888, ECO:0000269|PubMed:21314817, ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24371721, ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7923219, ECO:0000269|PubMed:9065413}. |
| Temperature Dependency | BIOPHYSICOCHEMICAL PROPERTIES: Temperature dependence: Optimum temperature is 37 degrees Celsius for gelatinase activity. Temperatures above 50 degrees Celsius inhibit gelatinase activity. {ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:9065413}; |
| PH Dependency | BIOPHYSICOCHEMICAL PROPERTIES: pH dependence: Optimum pH is 6-8.4 for gelatinase activity. At pH lower than 5 inhibited gelatinase activity. {ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:9065413}; |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Alternative sequence (1); Beta strand (50); Binding site (2); Chain (2); Disulfide bond (4); Glycosylation (6); Helix (19); Mutagenesis (10); Natural variant (1); Sequence conflict (3); Site (1); Topological domain (2); Transmembrane (1); Turn (7) |
| Keywords | 3D-structure;Alternative splicing;Angiogenesis;Apoptosis;Cell adhesion;Cell junction;Cell membrane;Cell projection;Cleavage on pair of basic residues;Cytoplasm;Direct protein sequencing;Disulfide bond;Glycoprotein;Hydrolase;Membrane;Protease;Reference proteome;Secreted;Serine protease;Signal-anchor;Transmembrane;Transmembrane helix |
| Interact With | P01275; P01282 |
| Induction | INDUCTION: In fibroblasts at times and sites of tissue remodeling during development, tissue repair and carcinogenesis. Up-regulated upon tumor stem cell differentiation. Up-regulated by transforming growth factor-beta, 12-O-tetradecanoyl phorbol-13-acetate and retinoids. {ECO:0000269|PubMed:20707604, ECO:0000269|PubMed:7519584}. |
| Subcellular Location | SUBCELLULAR LOCATION: [Prolyl endopeptidase FAP]: Cell surface {ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7911242}. Cell membrane {ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}; Single-pass type II membrane protein {ECO:0000255}. Cell projection, lamellipodium membrane {ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:9065413}; Single-pass type II membrane protein {ECO:0000255}. Cell projection, invadopodium membrane {ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:7923219, ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}; Single-pass type II membrane protein {ECO:0000255}. Cell projection, ruffle membrane {ECO:0000303|PubMed:10455171}; Single-pass type II membrane protein {ECO:0000255}. Membrane {ECO:0000269|PubMed:2172980}; Single-pass type II membrane protein {ECO:0000255}. Note=Localized on cell surface with lamellipodia and invadopodia membranes and on shed vesicles. Colocalized with DPP4 at invadopodia and lamellipodia membranes of migratory activated endothelial cells in collagenous matrix. Colocalized with DPP4 on endothelial cells of capillary-like microvessels but not large vessels within invasive breast ductal carcinoma. Anchored and enriched preferentially by integrin alpha-3/beta-1 at invadopodia, plasma membrane protrusions that correspond to sites of cell invasion, in a collagen-dependent manner. Localized at plasma and ruffle membranes in a collagen-independent manner. Colocalized with PLAUR preferentially at the cell surface of invadopodia membranes in a cytoskeleton-, integrin- and vitronectin-dependent manner. Concentrated at invadopodia membranes, specialized protrusions of the ventral plasma membrane in a fibrobectin-dependent manner. Colocalizes with extracellular components (ECM), such as collagen fibers and fibronectin. {ECO:0000269|PubMed:10593948, ECO:0000269|PubMed:12376466, ECO:0000269|PubMed:16175601, ECO:0000269|PubMed:16651416, ECO:0000269|PubMed:17105646, ECO:0000269|PubMed:2172980, ECO:0000269|PubMed:24717288, ECO:0000269|PubMed:7911242, ECO:0000269|PubMed:7923219, ECO:0000269|PubMed:9065413, ECO:0000303|PubMed:10455171}.; SUBCELLULAR LOCATION: [Antiplasmin-cleaving enzyme FAP, soluble form]: Secreted {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:24371721}. Note=Found in blood plasma and serum. {ECO:0000269|PubMed:14751930, ECO:0000269|PubMed:16223769, ECO:0000269|PubMed:24371721}.; SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm {ECO:0000303|PubMed:10644713}. |
| Modified Residue | |
| Post Translational Modification | PTM: N-glycosylated. {ECO:0000269|PubMed:15809306, ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:7911242, ECO:0000269|PubMed:9065413}.; PTM: The N-terminus may be blocked. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (2) |
| Cross Reference PDB | 1Z68; 6Y0F; |
| Mapped Pubmed ID | 12023964; 12675244; 12926053; 12963128; 14524536; 14707457; 15767544; 16061874; 16196122; 16507127; 16700525; 18071670; 18570153; 18665076; 18823010; 19747910; 20043068; 20155839; 20379614; 20711172; 20806341; 20872224; 21491083; 21526345; 21656680; 21668992; 22067528; 22323494; 22371645; 22435331; 22608558; 22614695; 22674411; 22734237; 22750443; 22911669; 23328994; 23778090; 23813624; 23835897; 23932048; 24402778; 24422232; 24470260; 24551161; 24595644; 24722280; 24727589; 24789592; 24885257; 25126747; 25361590; 25464232; 25600705; 25744843; 25775399; 25816202; 25995078; 26209915; 26304112; 26319660; 26342814; 26454160; 26621486; 26635356; 26715280; 26797127; 26934296; 26962859; 27020681; 27063470; 27118870; 27155568; 27492457; 27817025; 27881889; 27983931; 27990763; 28005267; 28033421; 28383825; 28415791; 28452380; 28570749; 28582421; 28612533; 28895412; 29025374; 29115573; 29134462; 29273462; 29361086; 29410133; 29663541; 29748183; 30383930; 30419872; 30468644; 30683902; 30922247; 31455871; 31745677; 31759251; 31885005; 31917931; 31991519; 32116236; 32344293; 32428869; 32733792; 32806623; 33109151; 33171480; 33416165; 33482262; 33706022; 33741330; 34035230; 34134455; 34201111; 34335962; |
| Motif | |
| Gene Encoded By | |
| Mass | 87,713 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=0.46 mM for Ala-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:10593948}; KM=0.9 mM for Lys-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:10593948}; KM=1.15 mM for Gly-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:10593948}; KM=0.25 mM for Gly-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:17381073}; KM=0.24 mM for Ala-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:16410248}; KM=0.10 mM for Ile-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:16410248}; KM=0.24 mM for Phe-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:16410248}; KM=0.24 mM for Gly-Pro (Dipeptidyl peptidase activity) {ECO:0000269|PubMed:16410248}; KM=0.33 mM for Ac-Gly-Pro (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16410248, ECO:0000269|PubMed:17381073}; KM=1.3 uM for Thr-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=2.2 uM for Ala-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=0.7 uM for Thr-Ala-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=1.9 uM for Thr-Ser-Gly-Pro-Ser-Gln (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=2.2 uM for Thr-Ser-Gly-Pro-Asn-Ser (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=4.3 uM for Ala-Ser-Gly-Pro-Ser-Ser (Prolyl endopeptidase activity) {ECO:0000269|PubMed:16480718}; KM=0.101 mM for Gly-Pro (FAP form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769}; KM=0.124 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769}; KM=0.323 mM for Gly-Pro (FAP form, dipeptidyl peptidase activity) {ECO:0000269|PubMed:16223769}; KM=0.272 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, dipeptidyl peptidase activity) {ECO:0000269|PubMed:16223769}; KM=0.029 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu (FAP form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769}; KM=0.026 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu (Antiplasmin-cleaving enzyme FAP soluble form, prolyl endopeptidase activity) {ECO:0000269|PubMed:16223769}; |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.21.B28; |