Q12884 (SEPR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Seprase
EC=3.4.21.-

Alternative name(s):
170 kDa melanoma membrane-bound gelatinase
Fibroblast activation protein alpha
Integral membrane serine protease

Gene names

Name:

FAP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	760 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	In association with DPP4 is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May have a role in tissue remodeling during development and wound healing, and may contribute to invasiveness in malignant cancers. Ref.10
Catalytic activity	Degrades gelatin and heat-denatured type I and type IV collagen, but not native type I or type IV collagen. Does not cleave laminin, fibronectin, fibrin or casein.
Subunit structure	Homodimer, or heterodimer with DPP4. The monomer is inactive. Ref.10 Ref.11
Subcellular location	Cell membrane; Single-pass type II membrane protein. Cell projection › lamellipodium membrane; Single-pass type II membrane protein. Cell projection › invadopodium membrane; Single-pass type II membrane protein. Note: Found in cell surface lamellipodia, invadopodia and on shed vesicles. Colocalized with DPP4 in invadopodia and lamellipodia 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. Ref.10
Tissue specificity	Fibroblast specific.
Induction	In fibroblasts at times and sites of tissue remodeling during development, tissue repair, and carcinogenesis.
Post-translational modification	N-glycosylated. Ref.11 The N-terminus may be blocked.
Sequence similarities	Belongs to the peptidase S9B family.

Ontologies

Keywords
Cellular component	Cell junction Cell membrane Cell projection Membrane
Coding sequence diversity	Alternative splicing
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	endothelial cell migration Inferred from direct assay Ref.10. Source: UniProtKB negative regulation of extracellular matrix disassembly Inferred from direct assay Ref.10. Source: UniProtKB proteolysis Inferred from electronic annotation. Source: UniProtKB-KW regulation of fibrinolysis Inferred by curator PubMed 17317851. Source: BHF-UCL
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW extracellular space Inferred from direct assay PubMed 17317851. Source: BHF-UCL integral to membrane Non-traceable author statement Ref.3. Source: UniProtKB invadopodium membrane Inferred from electronic annotation. Source: UniProtKB-SubCell lamellipodium Inferred from direct assay Ref.10Ref.3. Source: UniProtKB lamellipodium membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	dipeptidyl-peptidase activity Non-traceable author statement Ref.1. Source: UniProtKB metalloendopeptidase activity Traceable author statement Ref.3. Source: UniProtKB protein homodimerization activity Non-traceable author statement Ref.2. Source: UniProtKB serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro serine-type peptidase activity Inferred from direct assay Ref.10. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q12884-1)

Also known as: L;

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.

Note: Major isoform.

Isoform 2 (identifier: Q12884-2)

Also known as: S; Truncated;

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 760

760

Seprase

PRO_0000122424

Regions

Topological domain

1 – 4

4

Cytoplasmic Potential

Transmembrane

5 – 25

21

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

26 – 760

735

Extracellular Potential

Sites

Active site

624

1

Charge relay system Ref.11

Active site

702

1

Charge relay system Ref.11

Active site

734

1

Charge relay system Ref.11

Binding site

203

1

Substrate

Binding site

204

1

Substrate

Amino acid modifications

Glycosylation

49

1

N-linked (GlcNAc...) Ref.11

Glycosylation

92

1

N-linked (GlcNAc...) Ref.11

Glycosylation

99

1

N-linked (GlcNAc...) Ref.9

Glycosylation

227

1

N-linked (GlcNAc...) Ref.9 Ref.11

Glycosylation

314

1

N-linked (GlcNAc...) Ref.11

Glycosylation

679

1

N-linked (GlcNAc...) Potential

Disulfide bond

321 ↔ 332

Ref.11

Disulfide bond

438 ↔ 441

Ref.11

Disulfide bond

448 ↔ 466

Ref.11

Disulfide bond

643 ↔ 755

Ref.11

Natural variations

Alternative sequence

1 – 521

521

Missing in isoform 2.

VSP_005367

Experimental info

Sequence conflict

207

1

A → P in AAB49652. Ref.1

Sequence conflict

229

1

T → K in AAB49652. Ref.1

Sequence conflict

354

1

T → R in AAB49652. Ref.1

Secondary structure

1

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760

Helix Strand Turn

Details...

Helix

44 – 49

6

Turn

50 – 52

3

Beta strand

60 – 70

11

Beta strand

76 – 83

8

Beta strand

86 – 90

5

Helix

92 – 96

5

Turn

97 – 99

3

Beta strand

101 – 105

5

Beta strand

109 – 120

12

Beta strand

122 – 124

3

Beta strand

126 – 134

9

Turn

135 – 138

4

Beta strand

148 – 150

3

Beta strand

153 – 155

3

Beta strand

162 – 166

5

Beta strand

169 – 175

7

Turn

189 – 191

3

Beta strand

192 – 196

5

Helix

199 – 204

6

Beta strand

212 – 214

3

Beta strand

218 – 227

10

Beta strand

233 – 238

6

Beta strand

241 – 244

4

Beta strand

246 – 251

6

Beta strand

261 – 270

10

Helix

272 – 275

4

Helix

284 – 287

4

Beta strand

291 – 312

22

Beta strand

315 – 323

9

Beta strand

325 – 331

7

Helix

334 – 336

3

Beta strand

337 – 341

5

Beta strand

343 – 345

3

Beta strand

347 – 351

5

Beta strand

364 – 369

6

Beta strand

375 – 382

8

Beta strand

393 – 395

3

Beta strand

397 – 403

7

Beta strand

405 – 413

9

Helix

415 – 417

3

Beta strand

422 – 428

7

Beta strand

430 – 433

4

Beta strand

436 – 440

5

Turn

441 – 447

7

Beta strand

450 – 455

6

Helix

457 – 459

3

Beta strand

460 – 466

7

Beta strand

469 – 471

3

Beta strand

473 – 477

5

Beta strand

479 – 481

3

Beta strand

484 – 489

6

Helix

492 – 497

6

Beta strand

505 – 513

9

Beta strand

516 – 524

9

Beta strand

530 – 532

3

Beta strand

534 – 540

7

Helix

557 – 563

7

Beta strand

568 – 573

6

Beta strand

577 – 580

4

Helix

582 – 585

4

Helix

586 – 588

3

Helix

594 – 608

15

Beta strand

613 – 623

11

Helix

625 – 634

10

Beta strand

637 – 639

3

Beta strand

642 – 648

7

Turn

653 – 655

3

Helix

658 – 665

8

Turn

670 – 673

4

Helix

674 – 679

6

Helix

683 – 689

7

Beta strand

692 – 699

8

Beta strand

703 – 705

3

Helix

708 – 719

12

Beta strand

725 – 729

5

Helix

739 – 756

18

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (L) [UniParc]. Last modified March 23, 2010. Version 5. Checksum: 7FF817B5A4F75142	FASTA	760	87,713
	10 20 30 40 50 60 MKTWVKIVFG VATSAVLALL VMCIVLRPSR VHNSEENTMR ALTLKDILNG TFSYKTFFPN 70 80 90 100 110 120 WISGQEYLHQ SADNNIVLYN IETGQSYTIL SNRTMKSVNA SNYGLSPDRQ FVYLESDYSK 130 140 150 160 170 180 LWRYSYTATY YIYDLSNGEF VRGNELPRPI QYLCWSPVGS KLAYVYQNNI YLKQRPGDPP 190 200 210 220 230 240 FQITFNGREN KIFNGIPDWV YEEEMLATKY ALWWSPNGKF LAYAEFNDTD IPVIAYSYYG 250 260 270 280 290 300 DEQYPRTINI PYPKAGAKNP VVRIFIIDTT YPAYVGPQEV PVPAMIASSD YYFSWLTWVT 310 320 330 340 350 360 DERVCLQWLK RVQNVSVLSI CDFREDWQTW DCPKTQEHIE ESRTGWAGGF FVSTPVFSYD 370 380 390 400 410 420 AISYYKIFSD KDGYKHIHYI KDTVENAIQI TSGKWEAINI FRVTQDSLFY SSNEFEEYPG 430 440 450 460 470 480 RRNIYRISIG SYPPSKKCVT CHLRKERCQY YTASFSDYAK YYALVCYGPG IPISTLHDGR 490 500 510 520 530 540 TDQEIKILEE NKELENALKN IQLPKEEIKK LEVDEITLWY KMILPPQFDR SKKYPLLIQV 550 560 570 580 590 600 YGGPCSQSVR SVFAVNWISY LASKEGMVIA LVDGRGTAFQ GDKLLYAVYR KLGVYEVEDQ 610 620 630 640 650 660 ITAVRKFIEM GFIDEKRIAI WGWSYGGYVS SLALASGTGL FKCGIAVAPV SSWEYYASVY 670 680 690 700 710 720 TERFMGLPTK DDNLEHYKNS TVMARAEYFR NVDYLLIHGT ADDNVHFQNS AQIAKALVNA 730 740 750 760 QVDFQAMWYS DQNHGLSGLS TNHLYTHMTH FLKQCFSLSD
	Isoform 2 (S) (Truncated) [UniParc]. Checksum: 853731E1DF446AC6	FASTA	239	26,954
	10 20 30 40 50 60 MILPPQFDRS KKYPLLIQVY GGPCSQSVRS VFAVNWISYL ASKEGMVIAL VDGRGTAFQG 70 80 90 100 110 120 DKLLYAVYRK LGVYEVEDQI TAVRKFIEMG FIDEKRIAIW GWSYGGYVSS LALASGTGLF 130 140 150 160 170 180 KCGIAVAPVS SWEYYASVYT ERFMGLPTKD DNLEHYKNST VMARAEYFRN VDYLLIHGTA 190 200 210 220 230 DDNVHFQNSA QIAKALVNAQ VDFQAMWYSD QNHGLSGLST NHLYTHMTHF LKQCFSLSD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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). 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. 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] (ISOFORM 2). 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]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases 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]	"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.
[9]	"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, MASS SPECTROMETRY. Tissue: Plasma.
[10]	"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, HETERODIMERIZATION, SUBCELLULAR LOCATION.
[11]	"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, SUBUNIT, DISULFIDE BONDS, ACTIVE SITE, GLYCOSYLATION AT ASN-49; ASN-92; ASN-227 AND ASN-314.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00295461.
IPI00375396.

RefSeq

NP_004451.2. NM_004460.2.

UniGene

Hs.654370.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Z68	X-ray	2.60	A/B	39-757	[»]

ProteinModelPortal

Q12884.

SMR

Q12884. Positions 39-757.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q12884. 1 interaction.

STRING

9606.ENSP00000188790.

Protein family/group databases

MEROPS

S09.007.

PTM databases

PhosphoSite

Q12884.

Polymorphism databases

DMDM

292495099.

Proteomic databases

PaxDb

Q12884.

PRIDE

Q12884.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000188790; ENSP00000188790; ENSG00000078098.

GeneID

2191.

KEGG

hsa:2191.

UCSC

uc002ucd.3. human.
uc010fpc.3. human.

Organism-specific databases

CTD

2191.

GeneCards

GC02M163027.

H-InvDB

HIX0002548.

HGNC

HGNC:3590. FAP.

MIM

600403. gene.

neXtProt

NX_Q12884.

PharmGKB

PA28003.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1506.

HOGENOM

HOG000231875.

HOVERGEN

HBG005527.

InParanoid

Q12884.

KO

K08674.

OMA

LSTKHLY.

OrthoDB

EOG4CVG69.

PhylomeDB

Q12884.

Gene expression databases

ArrayExpress

Q12884.

Bgee

Q12884.

CleanEx

HS_FAP.

Genevestigator

Q12884.

GermOnline

ENSG00000078098. Homo sapiens.

Family and domain databases

InterPro

IPR002471. Pept_S9_AS.
IPR001375. Peptidase_S9.
IPR002469. Peptidase_S9B.
[Graphical view]

Pfam

PF00930. DPPIV_N. 1 hit.
PF00326. Peptidase_S9. 1 hit.
[Graphical view]

PROSITE

PS00708. PRO_ENDOPEP_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL4683.

ChiTaRS

FAP. human.

EvolutionaryTrace

Q12884.

GenomeRNAi

2191.

NextBio

8851.

SOURCE

Search...

Entry information

Entry name

SEPR_HUMAN

Accession

Primary (citable) accession number: Q12884
Secondary accession number(s): O00199 , Q53TP5, Q86Z29, Q99998, Q9UID4

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 5, 2002
Last sequence update:	March 23, 2010
Last modified:	April 3, 2013
This is version 135 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.