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Q12884

- SEPR_HUMAN

UniProt

Q12884 - SEPR_HUMAN

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Protein

Prolyl endopeptidase FAP

Gene

FAP

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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, vibronectin, tenascin, laminin, fibronectin, fibrin or casein (PubMed:9065413, PubMed:2172980, PubMed:7923219, PubMed:10347120, PubMed:10455171, PubMed:12376466, PubMed:16223769, PubMed:16651416, PubMed:18095711). 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 (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.By similarity21 Publications

Catalytic activityi

Hydrolysis of Pro-|-Xaa >> Ala-|-Xaa in oligopeptides.7 Publications
Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline.10 PublicationsPROSITE-ProRule annotation

Enzyme regulationi

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.6 Publications

Kineticsi

  1. KM=0.46 mM for Ala-Pro (Dipeptidyl peptidase activity)1 Publication
  2. KM=0.9 mM for Lys-Pro (Dipeptidyl peptidase activity)1 Publication
  3. KM=1.15 mM for Gly-Pro (Dipeptidyl peptidase activity)1 Publication
  4. KM=0.25 mM for Gly-Pro (Dipeptidyl peptidase activity)1 Publication
  5. KM=0.24 mM for Ala-Pro (Dipeptidyl peptidase activity)1 Publication
  6. KM=0.10 mM for Ile-Pro (Dipeptidyl peptidase activity)1 Publication
  7. KM=0.24 mM for Phe-Pro (Dipeptidyl peptidase activity)1 Publication
  8. KM=0.24 mM for Gly-Pro (Dipeptidyl peptidase activity)1 Publication
  9. KM=0.33 mM for Ac-Gly-Pro (Prolyl endopeptidase activity)2 Publications
  10. KM=1.3 µM for Thr-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)1 Publication
  11. KM=2.2 µM for Ala-Ser-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)1 Publication
  12. KM=0.7 µM for Thr-Ala-Gly-Pro-Asn-Gln (Prolyl endopeptidase activity)1 Publication
  13. KM=1.9 µM for Thr-Ser-Gly-Pro-Ser-Gln (Prolyl endopeptidase activity)1 Publication
  14. KM=2.2 µM for Thr-Ser-Gly-Pro-Asn-Ser (Prolyl endopeptidase activity)1 Publication
  15. KM=4.3 µM for Ala-Ser-Gly-Pro-Ser-Ser (Prolyl endopeptidase activity)1 Publication
  16. KM=0.101 mM for Gly-Pro (FAP form, prolyl endopeptidase activity)1 Publication
  17. KM=0.124 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, prolyl endopeptidase activity)1 Publication
  18. KM=0.323 mM for Gly-Pro (FAP form, dipeptidyl peptidase activity)1 Publication
  19. KM=0.272 mM for Gly-Pro (Antiplasmin-cleaving enzyme FAP soluble form, dipeptidyl peptidase activity)1 Publication
  20. KM=0.029 mM for Arg-Gly-Thr-Ser-Gly-Pro-Asn-Gln-Glu-Gln-Glu (FAP form, prolyl endopeptidase activity)1 Publication
  21. 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)1 Publication

pH dependencei

Optimum pH is 6-8.4 for gelatinase activity. At pH lower than 5 inhibited gelatinase activity.2 Publications

Temperature dependencei

Optimum temperature is 37 degrees Celsius for gelatinase activity. Temperatures above 50 degrees Celsius inhibit gelatinase activity.2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei23 – 242Cleavage1 Publication
Binding sitei203 – 2031Substrate1 Publication
Binding sitei204 – 2041Substrate1 Publication
Active sitei624 – 6241Charge relay system1 PublicationPROSITE-ProRule annotation
Active sitei702 – 7021Charge relay system1 Publication
Active sitei734 – 7341Charge relay system1 Publication

GO - Molecular functioni

  1. dipeptidyl-peptidase activity Source: UniProtKB
  2. endopeptidase activity Source: BHF-UCL
  3. integrin binding Source: UniProtKB
  4. metalloendopeptidase activity Source: UniProtKB
  5. peptidase activity Source: UniProtKB
  6. protease binding Source: BHF-UCL
  7. protein dimerization activity Source: UniProtKB
  8. protein homodimerization activity Source: UniProtKB
  9. serine-type endopeptidase activity Source: UniProtKB
  10. serine-type peptidase activity Source: UniProtKB

GO - Biological processi

  1. endothelial cell migration Source: UniProtKB
  2. melanocyte apoptotic process Source: UniProtKB
  3. melanocyte proliferation Source: UniProtKB
  4. mitotic cell cycle arrest Source: UniProtKB
  5. negative regulation of cell proliferation involved in contact inhibition Source: UniProtKB
  6. negative regulation of extracellular matrix disassembly Source: UniProtKB
  7. negative regulation of extracellular matrix organization Source: UniProtKB
  8. positive regulation of cell cycle arrest Source: UniProtKB
  9. positive regulation of execution phase of apoptosis Source: UniProtKB
  10. proteolysis Source: UniProtKB
  11. proteolysis involved in cellular protein catabolic process Source: UniProtKB
  12. regulation of collagen catabolic process Source: UniProtKB
  13. regulation of fibrinolysis Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Keywords - Biological processi

Angiogenesis, Apoptosis, Cell adhesion

Protein family/group databases

MEROPSiS09.007.

Names & Taxonomyi

Protein namesi
Recommended name:
Prolyl endopeptidase FAPCurated (EC:3.4.21.261 Publication)
Alternative name(s):
170 kDa melanoma membrane-bound gelatinase2 Publications
Dipeptidyl peptidase FAPCurated (EC:3.4.14.51 Publication)
Fibroblast activation protein alpha1 Publication
Short name:
FAPalphaBy similarity
Gelatine degradation protease FAPCurated (EC:3.4.21.-1 Publication)
Integral membrane serine protease1 Publication
Post-proline cleaving enzymeCurated
Serine integral membrane protease1 Publication
Short name:
SIMP1 Publication
Surface-expressed protease1 Publication
Short name:
Seprase1 Publication
Cleaved into the following chain:
Antiplasmin-cleaving enzyme FAP, soluble form1 Publication (EC:3.4.14.52 Publications, EC:3.4.21.-2 Publications, EC:3.4.21.262 Publications)
Short name:
APCE1 Publication
Gene namesi
Name:FAPImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:3590. FAP.

Subcellular locationi

Chain Prolyl endopeptidase FAP : Cell surface 5 Publications. Cell membrane 3 Publications1 Publication; Single-pass type II membrane protein Sequence Analysis. Cell projectionlamellipodium membrane 2 Publications; Single-pass type II membrane protein Sequence Analysis. Cell projectioninvadopodium membrane 4 Publications1 Publication; Single-pass type II membrane protein Sequence Analysis. Cell projectionruffle membrane 1 Publication; Single-pass type II membrane protein Sequence Analysis. Membrane 1 Publication; Single-pass type II membrane protein Sequence Analysis
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.10 Publications1 Publication
Chain Antiplasmin-cleaving enzyme FAP, soluble form : Secreted 3 Publications
Note: Found in blood plasma and serum.3 Publications
Isoform 2 : Cytoplasm 1 Publication

GO - Cellular componenti

  1. apical part of cell Source: Ensembl
  2. basal part of cell Source: Ensembl
  3. cell surface Source: UniProtKB
  4. extracellular space Source: BHF-UCL
  5. focal adhesion Source: UniProtKB
  6. integral component of membrane Source: UniProtKB
  7. invadopodium membrane Source: UniProtKB
  8. lamellipodium Source: UniProtKB
  9. plasma membrane Source: UniProtKB
  10. ruffle membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi123 – 1231R → A, M or E: Reduces dipeptidyl peptidase and endopeptidase activities. 1 Publication
Mutagenesisi203 – 2031E → A, D or Q: Reduces dipeptidyl peptidase and endopeptidase activities. Does not inhibit cell adhesion, migration and invasion. Inhibits dipeptidyl peptidase and endopeptidase activities; when associated with A-204. 2 Publications
Mutagenesisi204 – 2041E → A, D or Q: Reduces dipeptidyl peptidase and endopeptidase activities. Does not inhibit cell adhesion, migration and invasion. Inhibits dipeptidyl peptidase and endopeptidase activities; when associated with A-203. 2 Publications
Mutagenesisi624 – 6241S → A: Reduces dipeptidyl peptidase and gelatinolytic activities. Does not inhibit cell adhesion, migration and invasion. 2 Publications
Mutagenesisi656 – 6561Y → F: Reduces dipeptidyl peptidase and endopeptidase activities. 1 Publication
Mutagenesisi657 – 6571A → D or N: Inhibits endopeptidase activity. Increases dipeptidyl peptidase activity. 1 Publication
Mutagenesisi657 – 6571A → F or V: Reduces dipeptidyl peptidase and endopeptidase activities. 1 Publication
Mutagenesisi657 – 6571A → Q: Inhibits endopeptidase activity. No change in dipeptidyl peptidase activity. 1 Publication
Mutagenesisi657 – 6571A → S or T: Reduces strongly endopeptidase activity. No change in dipeptidyl peptidase activity. 1 Publication
Mutagenesisi704 – 7041N → A: Reduces dipeptidyl peptidase and endopeptidase activities. 1 Publication

Organism-specific databases

PharmGKBiPA28003.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 760760Prolyl endopeptidase FAPCuratedPRO_0000122424Add
BLAST
Chaini24 – 760737Antiplasmin-cleaving enzyme FAP, soluble form1 PublicationPRO_0000430643Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi49 – 491N-linked (GlcNAc...)1 PublicationPROSITE-ProRule annotation
Glycosylationi92 – 921N-linked (GlcNAc...)1 PublicationPROSITE-ProRule annotation
Glycosylationi99 – 991N-linked (GlcNAc...)1 PublicationPROSITE-ProRule annotation
Glycosylationi227 – 2271N-linked (GlcNAc...)2 PublicationsPROSITE-ProRule annotation
Glycosylationi314 – 3141N-linked (GlcNAc...)1 PublicationPROSITE-ProRule annotation
Disulfide bondi321 ↔ 3321 Publication
Disulfide bondi438 ↔ 4411 Publication
Disulfide bondi448 ↔ 4661 Publication
Disulfide bondi643 ↔ 7551 Publication
Glycosylationi679 – 6791N-linked (GlcNAc...)PROSITE-ProRule annotation

Post-translational modificationi

N-glycosylated.4 Publications
The N-terminus may be blocked.

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ12884.
PRIDEiQ12884.

PTM databases

PhosphoSiteiQ12884.

Expressioni

Tissue specificityi

Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines.8 Publications

Inductioni

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.2 Publications

Gene expression databases

BgeeiQ12884.
CleanExiHS_FAP.
ExpressionAtlasiQ12884. baseline and differential.
GenevestigatoriQ12884.

Organism-specific databases

HPAiHPA059739.

Interactioni

Subunit structurei

Homodimer; homodimerization is required for activity of both plasma membrane and soluble forms. The monomer is inactive. Heterodimer with DPP4. Interacts with PLAUR; the interaction occurs at the cell surface of invadopodia membranes. Interacts with ITGB1. Interacts with ITGA3. Associates with integrin alpha-3/beta-1; the association occurs in a collagen-dependent manner at the cell surface of invadopodia membranes.7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
GCGP012754EBI-4319803,EBI-7629173
VIPP012822EBI-4319803,EBI-751454

Protein-protein interaction databases

BioGridi108485. 4 interactions.
IntActiQ12884. 10 interactions.
MINTiMINT-4778828.
STRINGi9606.ENSP00000188790.

Structurei

Secondary structure

1
760
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi44 – 496
Turni50 – 523
Beta strandi60 – 7011
Beta strandi76 – 838
Beta strandi86 – 905
Helixi92 – 965
Turni97 – 993
Beta strandi101 – 1055
Beta strandi109 – 12012
Beta strandi122 – 1243
Beta strandi126 – 1349
Turni135 – 1384
Beta strandi148 – 1503
Beta strandi153 – 1553
Beta strandi162 – 1665
Beta strandi169 – 1757
Turni189 – 1913
Beta strandi192 – 1965
Helixi199 – 2046
Beta strandi212 – 2143
Beta strandi218 – 22710
Beta strandi233 – 2386
Beta strandi241 – 2444
Beta strandi246 – 2516
Beta strandi261 – 27010
Helixi272 – 2754
Helixi284 – 2874
Beta strandi291 – 31222
Beta strandi315 – 3239
Beta strandi325 – 3317
Helixi334 – 3363
Beta strandi337 – 3415
Beta strandi343 – 3453
Beta strandi347 – 3515
Beta strandi364 – 3696
Beta strandi375 – 3828
Beta strandi393 – 3953
Beta strandi397 – 4037
Beta strandi405 – 4139
Helixi415 – 4173
Beta strandi422 – 4287
Beta strandi430 – 4334
Beta strandi436 – 4405
Turni441 – 4477
Beta strandi450 – 4556
Helixi457 – 4593
Beta strandi460 – 4667
Beta strandi469 – 4713
Beta strandi473 – 4775
Beta strandi479 – 4813
Beta strandi484 – 4896
Helixi492 – 4976
Beta strandi505 – 5139
Beta strandi516 – 5249
Beta strandi530 – 5323
Beta strandi534 – 5407
Helixi557 – 5637
Beta strandi568 – 5736
Beta strandi577 – 5804
Helixi582 – 5854
Helixi586 – 5883
Helixi594 – 60815
Beta strandi613 – 62311
Helixi625 – 63410
Beta strandi637 – 6393
Beta strandi642 – 6487
Turni653 – 6553
Helixi658 – 6658
Turni670 – 6734
Helixi674 – 6796
Helixi683 – 6897
Beta strandi692 – 6998
Beta strandi703 – 7053
Helixi708 – 71912
Beta strandi725 – 7295
Helixi739 – 75618

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1Z68X-ray2.60A/B39-757[»]
ProteinModelPortaliQ12884.
SMRiQ12884. Positions 39-757.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ12884.

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 44Cytoplasmic1 PublicationSequence Analysis
Topological domaini26 – 760735Extracellular1 PublicationSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei5 – 2521Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
BLAST

Family & Domainsi

Sequence similaritiesi

Belongs to the peptidase S9B family.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG1506.
GeneTreeiENSGT00760000119233.
HOGENOMiHOG000231875.
HOVERGENiHBG005527.
InParanoidiQ12884.
KOiK08674.
OMAiQYYTARF.
OrthoDBiEOG761BT2.
PhylomeDBiQ12884.
TreeFamiTF313309.

Family and domain databases

Gene3Di2.140.10.30. 1 hit.
3.40.50.1820. 1 hit.
InterProiIPR029058. AB_hydrolase.
IPR002471. Pept_S9_AS.
IPR001375. Peptidase_S9.
IPR002469. Peptidase_S9B.
[Graphical view]
PfamiPF00930. DPPIV_N. 1 hit.
PF00326. Peptidase_S9. 1 hit.
[Graphical view]
SUPFAMiSSF53474. SSF53474. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q12884-1) [UniParc]FASTAAdd to Basket

Also known as: L, seprase-I1 Publication

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKTWVKIVFG VATSAVLALL VMCIVLRPSR VHNSEENTMR ALTLKDILNG
60 70 80 90 100
TFSYKTFFPN WISGQEYLHQ SADNNIVLYN IETGQSYTIL SNRTMKSVNA
110 120 130 140 150
SNYGLSPDRQ FVYLESDYSK LWRYSYTATY YIYDLSNGEF VRGNELPRPI
160 170 180 190 200
QYLCWSPVGS KLAYVYQNNI YLKQRPGDPP FQITFNGREN KIFNGIPDWV
210 220 230 240 250
YEEEMLATKY ALWWSPNGKF LAYAEFNDTD IPVIAYSYYG DEQYPRTINI
260 270 280 290 300
PYPKAGAKNP VVRIFIIDTT YPAYVGPQEV PVPAMIASSD YYFSWLTWVT
310 320 330 340 350
DERVCLQWLK RVQNVSVLSI CDFREDWQTW DCPKTQEHIE ESRTGWAGGF
360 370 380 390 400
FVSTPVFSYD AISYYKIFSD KDGYKHIHYI KDTVENAIQI TSGKWEAINI
410 420 430 440 450
FRVTQDSLFY SSNEFEEYPG RRNIYRISIG SYPPSKKCVT CHLRKERCQY
460 470 480 490 500
YTASFSDYAK YYALVCYGPG IPISTLHDGR TDQEIKILEE NKELENALKN
510 520 530 540 550
IQLPKEEIKK LEVDEITLWY KMILPPQFDR SKKYPLLIQV YGGPCSQSVR
560 570 580 590 600
SVFAVNWISY LASKEGMVIA LVDGRGTAFQ GDKLLYAVYR KLGVYEVEDQ
610 620 630 640 650
ITAVRKFIEM GFIDEKRIAI WGWSYGGYVS SLALASGTGL FKCGIAVAPV
660 670 680 690 700
SSWEYYASVY TERFMGLPTK DDNLEHYKNS TVMARAEYFR NVDYLLIHGT
710 720 730 740 750
ADDNVHFQNS AQIAKALVNA QVDFQAMWYS DQNHGLSGLS TNHLYTHMTH
760
FLKQCFSLSD

Note: Major isoform.

Length:760
Mass (Da):87,713
Last modified:March 23, 2010 - v5
Checksum:i7FF817B5A4F75142
GO
Isoform 21 Publication (identifier: Q12884-2) [UniParc]FASTAAdd to Basket

Also known as: S, Truncated, seprase-s1 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-521: Missing.

Note: Upstream open reading frames ORF(s)-containing region inhibits the translation of its downstream ORF.1 Publication

Show »
Length:239
Mass (Da):26,954
Checksum:i853731E1DF446AC6
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti207 – 2071A → P in AAB49652. (PubMed:7911242)Curated
Sequence conflicti229 – 2291T → K in AAB49652. (PubMed:7911242)Curated
Sequence conflicti354 – 3541T → R in AAB49652. (PubMed:7911242)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti363 – 3631S → L Decreased plasma membrane expression; loss of homodimerization and dipeptidyl peptidase activity; mislocalized with the calnexin in the endoplasmic reticulum; causes induction of the unfolded protein response (UPR). 2 Publications
VAR_071264

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 521521Missing in isoform 2. 1 PublicationVSP_005367Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U09278 mRNA. Translation: AAB49652.1.
U76833 mRNA. Translation: AAC51668.1.
AF007822 mRNA. Translation: AAF21600.1.
AC007750 Genomic DNA. Translation: AAY24205.1.
CH471058 Genomic DNA. Translation: EAX11353.1.
BC026250 mRNA. Translation: AAH26250.1.
CCDSiCCDS33311.1. [Q12884-1]
RefSeqiNP_001278736.1. NM_001291807.1.
NP_004451.2. NM_004460.3. [Q12884-1]
UniGeneiHs.654370.

Genome annotation databases

EnsembliENST00000188790; ENSP00000188790; ENSG00000078098. [Q12884-1]
GeneIDi2191.
KEGGihsa:2191.
UCSCiuc002ucd.3. human. [Q12884-1]
uc010fpc.3. human. [Q12884-2]

Polymorphism databases

DMDMi292495099.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U09278 mRNA. Translation: AAB49652.1 .
U76833 mRNA. Translation: AAC51668.1 .
AF007822 mRNA. Translation: AAF21600.1 .
AC007750 Genomic DNA. Translation: AAY24205.1 .
CH471058 Genomic DNA. Translation: EAX11353.1 .
BC026250 mRNA. Translation: AAH26250.1 .
CCDSi CCDS33311.1. [Q12884-1 ]
RefSeqi NP_001278736.1. NM_001291807.1.
NP_004451.2. NM_004460.3. [Q12884-1 ]
UniGenei Hs.654370.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1Z68 X-ray 2.60 A/B 39-757 [» ]
ProteinModelPortali Q12884.
SMRi Q12884. Positions 39-757.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 108485. 4 interactions.
IntActi Q12884. 10 interactions.
MINTi MINT-4778828.
STRINGi 9606.ENSP00000188790.

Chemistry

ChEMBLi CHEMBL4683.

Protein family/group databases

MEROPSi S09.007.

PTM databases

PhosphoSitei Q12884.

Polymorphism databases

DMDMi 292495099.

Proteomic databases

PaxDbi Q12884.
PRIDEi Q12884.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000188790 ; ENSP00000188790 ; ENSG00000078098 . [Q12884-1 ]
GeneIDi 2191.
KEGGi hsa:2191.
UCSCi uc002ucd.3. human. [Q12884-1 ]
uc010fpc.3. human. [Q12884-2 ]

Organism-specific databases

CTDi 2191.
GeneCardsi GC02M163027.
H-InvDB HIX0002548.
HGNCi HGNC:3590. FAP.
HPAi HPA059739.
MIMi 600403. gene.
neXtProti NX_Q12884.
PharmGKBi PA28003.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG1506.
GeneTreei ENSGT00760000119233.
HOGENOMi HOG000231875.
HOVERGENi HBG005527.
InParanoidi Q12884.
KOi K08674.
OMAi QYYTARF.
OrthoDBi EOG761BT2.
PhylomeDBi Q12884.
TreeFami TF313309.

Miscellaneous databases

ChiTaRSi FAP. human.
EvolutionaryTracei Q12884.
GeneWikii Fibroblast_activation_protein,_alpha.
GenomeRNAii 2191.
NextBioi 8851.
PROi Q12884.
SOURCEi Search...

Gene expression databases

Bgeei Q12884.
CleanExi HS_FAP.
ExpressionAtlasi Q12884. baseline and differential.
Genevestigatori Q12884.

Family and domain databases

Gene3Di 2.140.10.30. 1 hit.
3.40.50.1820. 1 hit.
InterProi IPR029058. AB_hydrolase.
IPR002471. Pept_S9_AS.
IPR001375. Peptidase_S9.
IPR002469. Peptidase_S9B.
[Graphical view ]
Pfami PF00930. DPPIV_N. 1 hit.
PF00326. Peptidase_S9. 1 hit.
[Graphical view ]
SUPFAMi SSF53474. SSF53474. 1 hit.
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers."
    Scanlan M.J., Raj B.K.M., Calvo B., Garin-Chesa P., Sanz-Moncasi M.P., Healey J.H., Old L.J., Rettig W.J.
    Proc. Natl. Acad. Sci. U.S.A. 91:5657-5661(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    Tissue: Fibroblast.
  2. "Molecular cloning of seprase: a serine integral membrane protease from human melanoma."
    Goldstein L.A., Ghersi G., Pineiro-Sanchez M.L., Salamone M., Yeh Y., Flessate D., Chen W.-T.
    Biochim. Biophys. Acta 1361:11-19(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Melanoma.
  3. "Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease."
    Pineiro-Sanchez M.L., Goldstein L.A., Dodt J., Howard L., Yeh Y., Chen W.-T.
    J. Biol. Chem. 272:7595-7601(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 220-229; 461-472 AND 511-518, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, SUBUNIT, GLYCOSYLATION, SUBCELLULAR LOCATION.
    Tissue: Melanoma.
  4. "Identification of an alternatively spliced seprase mRNA that encodes a novel intracellular isoform."
    Goldstein L.A., Chen W.-T.
    J. Biol. Chem. 275:2554-2559(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    Tissue: Melanoma.
  5. "Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
    Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H.
    , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
    Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  7. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Placenta.
  8. "A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion."
    Lee K.N., Jackson K.W., Christiansen V.J., Chung K.H., McKee P.A.
    Blood 103:3783-3788(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 24-38; 210-219; 247-254; 487-499; 500-509 AND 522-530, FUNCTION (SOLUBLE FORM), CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
  9. "Fibroblast activation protein: purification, epitope mapping and induction by growth factors."
    Rettig W.J., Su S.L., Fortunato S.R., Scanlan M.J., Raj B.K.M., Garin-Chesa P., Healey J.H., Old L.J.
    Int. J. Cancer 58:385-392(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 192-208; 220-240 AND 510-521, INDUCTION.
  10. "A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells."
    Aoyama A., Chen W.T.
    Proc. Natl. Acad. Sci. U.S.A. 87:8296-8300(1990) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES.
  11. "A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells."
    Monsky W.L., Lin C.Y., Aoyama A., Kelly T., Akiyama S.K., Mueller S.C., Chen W.T.
    Cancer Res. 54:5702-5710(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
  12. "Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis."
    Levy M.T., McCaughan G.W., Abbott C.A., Park J.E., Cunningham A.M., Mueller E., Rettig W.J., Gorrell M.D.
    Hepatology 29:1768-1778(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY.
  13. "Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts."
    Park J.E., Lenter M.C., Zimmermann R.N., Garin-Chesa P., Old L.J., Rettig W.J.
    J. Biol. Chem. 274:36505-36512(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF SER-624.
  14. Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, INTERACTION WITH ITGA3 AND ITGB1, ASSOCIATION WITH INTEGRIN ALPHA-3/BETA-1, SUBCELLULAR LOCATION.
  15. "Molecular proximity of seprase and the urokinase-type plasminogen activator receptor on malignant melanoma cell membranes: dependence on beta1 integrins and the cytoskeleton."
    Artym V.V., Kindzelskii A.L., Chen W.T., Petty H.R.
    Carcinogenesis 23:1593-1601(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PLAUR, SUBCELLULAR LOCATION.
  16. "Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line."
    Wang X.M., Yu D.M., McCaughan G.W., Gorrell M.D.
    Hepatology 42:935-945(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF GLU-203; GLU-204 AND SER-624.
  17. "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry."
    Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D.
    J. Proteome Res. 4:2070-2080(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-99 AND ASN-227.
    Tissue: Plasma.
  18. "Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes."
    Bauer S., Jendro M.C., Wadle A., Kleber S., Stenner F., Dinser R., Reich A., Faccin E., Goedde S., Dinges H., Mueller-Ladner U., Renner C.
    Arthritis Res. Ther. 8:R171-R171(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  19. "Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein."
    Lee K.N., Jackson K.W., Christiansen V.J., Lee C.S., Chun J.G., McKee P.A.
    Blood 107:1397-1404(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION (PLASMA MEMBRANE AND SOLUBLE FORMS), CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, SUBCELLULAR LOCATION.
  20. "The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices."
    Ghersi G., Zhao Q., Salamone M., Yeh Y., Zucker S., Chen W.T.
    Cancer Res. 66:4652-4661(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, HETERODIMERIZATION WITH DPP4, SUBCELLULAR LOCATION.
  21. "Peptide substrate profiling defines fibroblast activation protein as an endopeptidase of strict Gly(2)-Pro(1)-cleaving specificity."
    Edosada C.Y., Quan C., Tran T., Pham V., Wiesmann C., Fairbrother W., Wolf B.B.
    FEBS Lett. 580:1581-1586(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
  22. "Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity."
    Edosada C.Y., Quan C., Wiesmann C., Tran T., Sutherlin D., Reynolds M., Elliott J.M., Raab H., Fairbrother W., Wolf B.B.
    J. Biol. Chem. 281:7437-7444(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, SUBUNIT.
  23. "Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization."
    Meadows S.A., Edosada C.Y., Mayeda M., Tran T., Quan C., Raab H., Wiesmann C., Wolf B.B.
    Biochemistry 46:4598-4605(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF ARG-123; GLU-203; TYR-656; ALA-657 AND ASN-704, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
  24. "Fibroblast activation protein peptide substrates identified from human collagen I derived gelatin cleavage sites."
    Aggarwal S., Brennen W.N., Kole T.P., Schneider E., Topaloglu O., Yates M., Cotter R.J., Denmeade S.R.
    Biochemistry 47:1076-1086(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY.
  25. "Seprase: an overview of an important matrix serine protease."
    O'Brien P., O'Connor B.F.
    Biochim. Biophys. Acta 1784:1130-1145(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW, FUNCTION.
  26. "Expression and role of the cell surface protease seprase/fibroblast activation protein-alpha (FAP-alpha) in astroglial tumors."
    Mentlein R., Hattermann K., Hemion C., Jungbluth A.A., Held-Feindt J.
    Biol. Chem. 392:199-207(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION.
  27. "Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-alpha."
    Keane F.M., Nadvi N.A., Yao T.W., Gorrell M.D.
    FEBS J. 278:1316-1332(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY.
  28. "Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate."
    Huang C.H., Suen C.S., Lin C.T., Chien C.H., Lee H.Y., Chung K.M., Tsai T.Y., Jiaang W.T., Hwang M.J., Chen X.
    J. Biochem. 149:685-692(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY.
  29. Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANT LEU-363.
  30. "A rare variant in human fibroblast activation protein associated with ER stress, loss of enzymatic function and loss of cell surface localisation."
    Osborne B., Yao T.W., Wang X.M., Chen Y., Kotan L.D., Nadvi N.A., Herdem M., McCaughan G.W., Allen J.D., Yu D.M., Topaloglu A.K., Gorrell M.D.
    Biochim. Biophys. Acta 1844:1248-1259(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT LEU-363.
  31. "Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha."
    Aertgeerts K., Levin I., Shi L., Snell G.P., Jennings A., Prasad G.S., Zhang Y., Kraus M.L., Salakian S., Sridhar V., Wijnands R., Tennant M.G.
    J. Biol. Chem. 280:19441-19444(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 39-757, SUBSTRATE BINDING, SUBUNIT, DISULFIDE BONDS, ACTIVE SITE, GLYCOSYLATION AT ASN-49; ASN-92; ASN-227 AND ASN-314.

Entry informationi

Entry nameiSEPR_HUMAN
AccessioniPrimary (citable) accession number: Q12884
Secondary accession number(s): O00199
, Q53TP5, Q86Z29, Q99998, Q9UID4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 5, 2002
Last sequence update: March 23, 2010
Last modified: October 29, 2014
This is version 149 of the entry and version 5 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3