FAP - Prolyl endopeptidase FAP - human protein (Function)
 
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FAP »  Prolyl endopeptidase FAP   [ EC 3.4.21.26 ]
 
Protein also known as:  170 kDa melanoma membrane-bound gelatinase. Cleaved into:  Antiplasmin-cleaving enzyme FAP, soluble form.
Gene name:  FAP
Family name: Peptidase S9B
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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 (PubMed14751930, PubMed16223769, PubMed16480718, PubMed16410248, PubMed17381073, PubMed18095711, PubMed21288888, PubMed24371721). Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed9065413, PubMed2172980, PubMed7923219, PubMed10347120, PubMed10455171, PubMed12376466, PubMed16223769, PubMed16651416, PubMed18095711). Have also 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 (PubMed10347120, PubMed10593948, PubMed16175601, PubMed16223769, PubMed16651416, PubMed16410248, PubMed17381073, PubMed21314817, PubMed24371721, PubMed24717288). Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB) (PubMed21314817). 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.  
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  • UniProtKB
GO molecular function 
Dipeptidyl-peptidase activitydefinition[GO:0008239]  
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  • UniProtKB
Endopeptidase activitydefinition[GO:0004175]  
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  • BHF-UCL
Integrin bindingdefinition[GO:0005178]  
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  • UniProtKB
Metalloendopeptidase activitydefinition[GO:0004222]  
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  • UniProtKB
Peptidase activitydefinition[GO:0008233]  
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  • UniProtKB
  • MGI
Protease bindingdefinition[GO:0002020]  
1
  • BHF-UCL
Protein bindingdefinition[GO:0005515]  
2
  • IntAct
  • UniProtKB
Protein dimerization activitydefinition[GO:0046983]  
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  • UniProtKB
Protein homodimerization activitydefinition[GO:0042803]  
2
  • UniProtKB
Serine-type endopeptidase activitydefinition[GO:0004252]  
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  • UniProtKB
Serine-type peptidase activitydefinition[GO:0008236]  
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  • UniProtKB
  • BHF-UCL
GO biological process 
Angiogenesisdefinition[GO:0001525]  
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  • UniProtKB KW
Cell adhesiondefinition[GO:0007155]  
1
  • UniProtKB KW
Endothelial cell migrationdefinition[GO:0043542]  
1
  • UniProtKB
Melanocyte apoptotic processdefinition[GO:1902362]  
1
  • Ortholog Curator
Melanocyte proliferationdefinition[GO:0097325]  
1
  • Ortholog Curator
Mitotic cell cycle arrestdefinition[GO:0071850]  
1
  • Ortholog Curator
Negative regulation of cell proliferation involved in contact inhibitiondefinition[GO:0060244]  
1
  • Ortholog Curator
Negative regulation of extracellular matrix disassemblydefinition[GO:0010716]  
1
  • UniProtKB
Negative regulation of extracellular matrix organizationdefinition[GO:1903054]  
1
  • UniProtKB
Positive regulation of cell cycle arrestdefinition[GO:0071158]  
1
  • Ortholog Curator
Positive regulation of execution phase of apoptosisdefinition[GO:1900119]  
1
  • Ortholog Curator
Proteolysisdefinition[GO:0006508]  
1
  • UniProtKB
Proteolysis involved in cellular protein catabolic processdefinition[GO:0051603]  
1
  • UniProtKB
Regulation of collagen catabolic processdefinition[GO:0010710]  
1
  • UniProtKB
Regulation of fibrinolysisdefinition[GO:0051917]  
1
  • BHF-UCL
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reactions
EC 3.4.21.26: Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides.  
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  • UniProtKB
EC 3.4.14.5: Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline.  
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  • UniProtKB
  • PROSITE-ProRule
It is regulated in the following manner
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.  
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  • UniProtKB
 
More information is available from:
 

Biophysicochemical properties

Kinetic parameters
KM 0.10 mM for Ile-Pro (Dipeptidyl peptidase activity)
KM 0.24 mM for Ala-Pro (Dipeptidyl peptidase activity)
KM 2.2 uM for Thr-Ser-Gly-Pro-Asn-Ser (Prolyl endopeptidase activity)
KM 1.15 mM for Gly-Pro (Dipeptidyl peptidase activity)
KM 0.33 mM for Ac-Gly-Pro (Prolyl endopeptidase activity)
KM 0.25 mM for Gly-Pro (Dipeptidyl peptidase activity)
KM 0.272 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, dipeptidyl peptidase activity)
KM 1.3 uM for Thr-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
KM 1.9 uM for Thr-Ser-Gly-Pro-Ser-Gln (Prolyl endopeptidase activity)
KM 0.323 mM for Gly-Pro (FAP form, dipeptidyl peptidase activity)
KM 2.2 uM for Ala-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
KM 4.3 uM for Ala-Ser-Gly-Pro-Ser-Ser (Prolyl endopeptidase activity)
KM 0.7 uM for Thr-Ala-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)
KM 0.124 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, prolyl endopeptidase activity)
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)
KM 0.101 mM for Gly-Pro (FAP form, prolyl endopeptidase activity)
KM 0.24 mM for Gly-Pro (Dipeptidyl peptidase activity)
KM 0.029 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu (FAP form, prolyl endopeptidase activity)
KM 0.46 mM for Ala-Pro (Dipeptidyl peptidase activity)
KM 0.24 mM for Phe-Pro (Dipeptidyl peptidase activity)
KM 0.9 mM for Lys-Pro (Dipeptidyl peptidase activity)
Dependence
pH Optimum pH is 6-8.4 for gelatinase activity. At pH lower than 5 inhibited gelatinase activity.
Temperature Optimum temperature is 37 degrees Celsius for gelatinase activity. Temperatures above 50 degrees Celsius inhibit gelatinase activity.

Keywords

Biological process 
Angiogenesis  definition   [KW-0037]
Apoptosis  definition   [KW-0053]
Cell adhesion  definition   [KW-0130]
Molecular function 
Hydrolase  definition   [KW-0378]
Protease  definition   [KW-0645]
Serine protease  definition   [KW-0720]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links