Q04756 (HGFA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hepatocyte growth factor activator
Short name=HGF activator
Short name=HGFA
EC=3.4.21.-

Cleaved into the following 2 chains:

1. Hepatocyte growth factor activator short chain
2. Hepatocyte growth factor activator long chain

Gene names

Name:

HGFAC

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	655 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Activates hepatocyte growth factor (HGF) by converting it from a single chain to a heterodimeric form.
Subunit structure	Heterodimer of a short chain and a long chain linked by a disulfide bond.
Subcellular location	Secreted. Note: Secreted as an inactive single-chain precursor and is then activated to a heterodimeric form.
Tissue specificity	Liver.
Sequence similarities	Belongs to the peptidase S1 family. Contains 2 EGF-like domains. Contains 1 fibronectin type-I domain. Contains 1 fibronectin type-II domain. Contains 1 kringle domain. Contains 1 peptidase S1 domain.
Caution	It is uncertain whether Met-1 is the initiator.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	EGF-like domain Kringle Repeat Signal
Molecular function	Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	proteolysis Traceable author statement PubMed 8226803. Source: ProtInc
Cellular_component	extracellular region Non-traceable author statement PubMed 14718574. Source: UniProtKB extracellular space Inferred from electronic annotation. Source: InterPro rough endoplasmic reticulum Inferred from electronic annotation. Source: Compara
Molecular_function	serine-type endopeptidase activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 35

35

Ref.6

Propeptide

36 – 372

337

Removed in mature form

PRO_0000027911

Chain

373 – 407

35

Hepatocyte growth factor activator short chain

PRO_0000027912

Chain

408 – 655

248

Hepatocyte growth factor activator long chain

PRO_0000027913

Regions

Domain

103 – 150

48

Fibronectin type-II

Domain

160 – 198

39

EGF-like 1

Domain

200 – 240

41

Fibronectin type-I

Domain

241 – 279

39

EGF-like 2

Domain

286 – 367

82

Kringle

Domain

408 – 646

239

Peptidase S1

Sites

Active site

447

1

Charge relay system Ref.9

Active site

497

1

Charge relay system Ref.9

Active site

598

1

Charge relay system Ref.9

Amino acid modifications

Glycosylation

48

1

N-linked (GlcNAc...) Potential

Glycosylation

290

1

N-linked (GlcNAc...) Potential

Glycosylation

468

1

N-linked (GlcNAc...) Ref.7 Ref.8 Ref.10

Glycosylation

492

1

N-linked (GlcNAc...) Potential

Glycosylation

546

1

N-linked (GlcNAc...) Potential

Disulfide bond

108 ↔ 133

By similarity

Disulfide bond

122 ↔ 148

By similarity

Disulfide bond

164 ↔ 175

By similarity

Disulfide bond

169 ↔ 186

By similarity

Disulfide bond

188 ↔ 197

By similarity

Disulfide bond

202 ↔ 230

By similarity

Disulfide bond

228 ↔ 237

By similarity

Disulfide bond

245 ↔ 256

By similarity

Disulfide bond

250 ↔ 267

By similarity

Disulfide bond

269 ↔ 278

By similarity

Disulfide bond

286 ↔ 367

By similarity

Disulfide bond

307 ↔ 349

By similarity

Disulfide bond

338 ↔ 362

By similarity

Disulfide bond

394 ↔ 521

Interchain (between short and long chains) Ref.9 Ref.10

Disulfide bond

432 ↔ 448

Ref.9 Ref.10

Disulfide bond

440 ↔ 510

Ref.9 Ref.10

Disulfide bond

535 ↔ 604

Ref.9 Ref.10

Disulfide bond

567 ↔ 583

Ref.9 Ref.10

Disulfide bond

594 ↔ 622

Ref.9 Ref.10

Natural variations

Natural variant

218

1

A → S.
Corresponds to variant rs3748034 [ dbSNP | Ensembl ].

VAR_051851

Natural variant

225

1

V → M.
Corresponds to variant rs16844370 [ dbSNP | Ensembl ].

VAR_033651

Natural variant

231

1

F → L. Ref.5
Corresponds to variant rs1987546 [ dbSNP | Ensembl ].

VAR_033652

Natural variant

509

1

R → H.
Corresponds to variant rs16844401 [ dbSNP | Ensembl ].

VAR_024294

Natural variant

644

1

R → Q.
Corresponds to variant rs2498323 [ dbSNP | Ensembl ].

VAR_024295

Secondary structure

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655

Helix Strand Turn

Details...

Beta strand

422 – 427

6

Beta strand

430 – 438

9

Beta strand

441 – 444

4

Helix

446 – 449

4

Helix

455 – 457

3

Beta strand

458 – 463

6

Beta strand

475 – 477

3

Beta strand

479 – 484

6

Turn

493 – 496

4

Beta strand

499 – 503

5

Beta strand

506 – 508

3

Beta strand

509 – 511

3

Beta strand

514 – 516

3

Beta strand

534 – 541

8

Beta strand

543 – 547

5

Beta strand

555 – 561

7

Helix

564 – 567

4

Turn

570 – 573

4

Helix

574 – 576

3

Beta strand

581 – 585

5

Beta strand

587 – 589

3

Turn

595 – 599

5

Beta strand

601 – 606

6

Beta strand

609 – 618

10

Turn

621 – 623

3

Beta strand

625 – 627

3

Beta strand

629 – 633

5

Helix

634 – 637

4

Helix

638 – 644

7

Sequences

	Sequence		Length	Mass (Da)
	Q04756 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 2CF72F1E1B862ED7	FASTA	655	70,682
	10 20 30 40 50 60 MGRWAWVPSP WPPPGLGPFL LLLLLLLLLP RGFQPQPGGN RTESPEPNAT ATPAIPTILV 70 80 90 100 110 120 TSVTSETPAT SAPEAEGPQS GGLPPPPRAV PSSSSPQAQA LTEDGRPCRF PFRYGGRMLH 130 140 150 160 170 180 ACTSEGSAHR KWCATTHNYD RDRAWGYCVE ATPPPGGPAA LDPCASGPCL NGGSCSNTQD 190 200 210 220 230 240 PQSYHCSCPR AFTGKDCGTE KCFDETRYEY LEGGDRWARV RQGHVEQCEC FGGRTWCEGT 250 260 270 280 290 300 RHTACLSSPC LNGGTCHLIV ATGTTVCACP PGFAGRLCNI EPDERCFLGN GTGYRGVAST 310 320 330 340 350 360 SASGLSCLAW NSDLLYQELH VDSVGAAALL GLGPHAYCRN PDNDERPWCY VVKDSALSWE 370 380 390 400 410 420 YCRLEACESL TRVQLSPDLL ATLPEPASPG RQACGRRHKK RTFLRPRIIG GSSSLPGSHP 430 440 450 460 470 480 WLAAIYIGDS FCAGSLVHTC WVVSAAHCFS HSPPRDSVSV VLGQHFFNRT TDVTQTFGIE 490 500 510 520 530 540 KYIPYTLYSV FNPSDHDLVL IRLKKKGDRC ATRSQFVQPI CLPEPGSTFP AGHKCQIAGW 550 560 570 580 590 600 GHLDENVSGY SSSLREALVP LVADHKCSSP EVYGADISPN MLCAGYFDCK SDACQGDSGG 610 620 630 640 650 PLACEKNGVA YLYGIISWGD GCGRLHKPGV YTRVANYVDW INDRIRPPRR LVAPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and sequence analysis of the cDNA for a human serine protease responsible for activation of hepatocyte growth factor. Structural similarity of the protease precursor to blood coagulation factor XII." Miyazawa K., Shimomura T., Kitamura A., Kondo J., Morimoto Y., Kitamura N. J. Biol. Chem. 268:10024-10028(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Liver and Serum.
[2]	"Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene -- phylogenetic and functional relationship with blood coagulation factor XII, urokinase, and tissue-type plasminogen activator." Miyazawa K., Wang Y., Minoshima S., Shimizu N., Kitamura N. Eur. J. Biochem. 258:355-361(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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].
[4]	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].
[5]	"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], VARIANT LEU-231. Tissue: Liver.
[6]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 36-50.
[7]	"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-468, MASS SPECTROMETRY. Tissue: Plasma.
[8]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-468, MASS SPECTROMETRY. Tissue: Liver.
[9]	"Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B." Shia S., Stamos J., Kirchhofer D., Fan B., Wu J., Corpuz R.T., Santell L., Lazarus R.A., Eigenbrot C. J. Mol. Biol. 346:1335-1349(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 373-655 ALONE AND IN COMPLEX WITH INHIBITOR HAI1B, ACTIVE SITE, DISULFIDE BONDS.
[10]	"Structural insight into distinct mechanisms of protease inhibition by antibodies." Wu Y., Eigenbrot C., Liang W.C., Stawicki S., Shia S., Fan B., Ganesan R., Lipari M.T., Kirchhofer D. Proc. Natl. Acad. Sci. U.S.A. 104:19784-19789(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 373-655 IN COMPLEX WITH ANTIBODY, GLYCOSYLATION AT ASN-468, DISULFIDE BONDS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D14012 mRNA. Translation: BAA03113.1.
BC112190 mRNA. Translation: AAI12191.1.
D50030 Genomic DNA. Translation: BAA74450.1.
AL590235 Genomic DNA. Translation: CAM21456.1.
CH471131 Genomic DNA. Translation: EAW82464.1.
BC112192 mRNA. Translation: AAI12193.1.

IPI

IPI00029193.

PIR

A46688.

RefSeq

NP_001519.1. NM_001528.2.

UniGene

Hs.104.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1YBW	X-ray	2.70	A/B	373-655	[»]
1YC0	X-ray	2.60	A	373-655	[»]
2R0K	X-ray	3.51	A	373-655	[»]
2R0L	X-ray	2.20	A	408-655	[»]
			B	373-407	[»]
2WUB	X-ray	2.90	A/C	408-655	[»]
			B/D	373-407	[»]
2WUC	X-ray	2.70	A	408-655	[»]
			B	373-407	[»]
3K2U	X-ray	2.35	A	408-655	[»]
			B	373-407	[»]

ProteinModelPortal

Q04756.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-6022N.

IntAct

Q04756. 1 interaction.

STRING

9606.ENSP00000372224.

Protein family/group databases

MEROPS

S01.228.

PTM databases

PhosphoSite

Q04756.

Polymorphism databases

DMDM

547643.

Proteomic databases

PaxDb

Q04756.

PeptideAtlas

Q04756.

PRIDE

Q04756.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000382774; ENSP00000372224; ENSG00000109758.

GeneID

3083.

KEGG

hsa:3083.

UCSC

uc003ghc.3. human.

Organism-specific databases

CTD

3083.

GeneCards

GC04P003443.

HGNC

HGNC:4894. HGFAC.

HPA

CAB005215.

MIM

604552. gene.

neXtProt

NX_Q04756.

PharmGKB

PA29270.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5640.

HOGENOM

HOG000237314.

HOVERGEN

HBG004345.

InParanoid

Q04756.

KO

K09631.

OrthoDB

EOG4PK27Q.

PhylomeDB

Q04756.

Gene expression databases

ArrayExpress

Q04756.

Bgee

Q04756.

CleanEx

HS_HGFAC.

Genevestigator

Q04756.

GermOnline

ENSG00000109758. Homo sapiens.

Family and domain databases

Gene3D

2.10.10.10. 1 hit.
2.40.20.10. 1 hit.

InterPro

IPR014394. Coagulation_fac_XIIa/HGFA.
IPR000742. EG-like_dom.
IPR013032. EGF-like_CS.
IPR000083. Fibronectin_type1.
IPR000562. FN_type2_col-bd.
IPR000001. Kringle.
IPR013806. Kringle-like.
IPR018056. Kringle_CS.
IPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00008. EGF. 2 hits.
PF00039. fn1. 1 hit.
PF00040. fn2. 1 hit.
PF00051. Kringle. 1 hit.
PF00089. Trypsin. 1 hit.
[Graphical view]

PIRSF

PIRSF001146. Factor_XII_HGFA. 1 hit.

PRINTS

PR00722. CHYMOTRYPSIN.

SMART

SM00181. EGF. 2 hits.
SM00058. FN1. 1 hit.
SM00059. FN2. 1 hit.
SM00130. KR. 1 hit.
SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF57440. Kringle-like. 2 hits.
SSF50494. Pept_Ser_Cys. 1 hit.

PROSITE

PS00022. EGF_1. 2 hits.
PS01186. EGF_2. 1 hit.
PS50026. EGF_3. 2 hits.
PS01253. FN1_1. 1 hit.
PS51091. FN1_2. 1 hit.
PS00023. FN2_1. 1 hit.
PS51092. FN2_2. 1 hit.
PS00021. KRINGLE_1. 1 hit.
PS50070. KRINGLE_2. 1 hit.
PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q04756.

GenomeRNAi

3083.

NextBio

12223.

PMAP-CutDB

Q04756.

SOURCE

Search...

Entry information

Entry name

HGFA_HUMAN

Accession

Primary (citable) accession number: Q04756
Secondary accession number(s): Q14726, Q2M1W7, Q53X47

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 134 of the entry and version 1 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.