Q92743 (HTRA1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine protease HTRA1
EC=3.4.21.-

Alternative name(s):
High-temperature requirement A serine peptidase 1
L56
Serine protease 11

Gene names

Name:	HTRA1
Synonyms:	HTRA, PRSS11

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	480 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	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets. Ref.4 Ref.6 Ref.9
Subunit structure	Forms homotrimers. In the presence of substrate, may form higher-order multimers in a PDZ-independent manner. Interacts with TGF-beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5 By similarity. Ref.11
Subcellular location	Secreted. Cytoplasm › cytosol. Note: Predominantly secreted. Also found associated with the plasma membrane. Ref.4 Ref.5 Ref.9 Ref.11
Tissue specificity	Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level). Ref.4 Ref.5 Ref.6
Developmental stage	In the placenta, in the first trimester of gestation, low expression in the cells surrounding villi both in the inner layer of the cytotrophoblast and in the outer layer of the syncytiotrophoblast (at protein level). In the third trimester of gestation, very strong expression in the outer layer forming the syncytiotrophoblast and lower in the cytotrophoblast (at protein level). Ref.5
Domain	The IGFBP N-terminal domain mediates interaction with TSC2 substrate.
Involvement in disease	Age-related macular degeneration 7 (ARMD7) [MIM:610149]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.7 Ref.8 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, autosomal recessive (CARASIL) [MIM:600142]: A cerebrovascular disease characterized by non-hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12
Sequence similarities	Belongs to the peptidase S1B family. Contains 1 IGFBP N-terminal domain. Contains 1 Kazal-like domain. Contains 1 PDZ (DHR) domain.

Ontologies

Keywords
Cellular component	Cytoplasm Secreted
Disease	Age-related macular degeneration Disease mutation
Domain	Signal
Ligand	Growth factor binding
Molecular function	Hydrolase Protease Serine protease
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of BMP signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of transforming growth factor beta receptor signaling pathway Inferred from electronic annotation. Source: Compara proteolysis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell growth Inferred from electronic annotation. Source: InterPro
Cellular_component	cytosol Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Traceable author statement Ref.4. Source: ProtInc
Molecular_function	serine-type endopeptidase activity Traceable author statement Ref.4. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Potential

Chain

23 – 480

458

Serine protease HTRA1

PRO_0000026943

Regions

Domain

33 – 100

68

IGFBP N-terminal

Domain

98 – 157

60

Kazal-like

Domain

365 – 467

103

PDZ

Region

204 – 364

161

Serine protease

Sites

Active site

220

1

Charge relay system Potential

Active site

250

1

Charge relay system Potential

Active site

328

1

Charge relay system

Site

169

1

Involved in trimer stabilization

Site

171

1

Involved in trimer stabilization

Site

278

1

Involved in trimer stabilization

Natural variations

Natural variant

252

1

A → T in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. Ref.12
Corresponds to variant rs113993968 [ dbSNP | Ensembl ].

VAR_063148

Natural variant

297

1

V → M in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. Ref.12
Corresponds to variant rs113993969 [ dbSNP | Ensembl ].

VAR_063149

Experimental info

Mutagenesis

328

1

S → A: Loss of activity. Ref.4 Ref.11

Sequence conflict

323

1

I → T in AAC97211. Ref.4

Secondary structure

1

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480

Helix Strand Turn

Details...

Helix

43 – 45

3

Beta strand

57 – 59

3

Beta strand

65 – 68

4

Beta strand

74 – 77

4

Beta strand

87 – 90

4

Beta strand

108 – 113

6

Beta strand

118 – 123

6

Beta strand

125 – 128

4

Helix

129 – 141

13

Helix

165 – 168

4

Helix

171 – 179

9

Helix

180 – 182

3

Beta strand

183 – 191

9

Beta strand

193 – 196

4

Beta strand

198 – 208

11

Turn

211 – 213

3

Beta strand

214 – 218

5

Turn

219 – 221

3

Beta strand

224 – 231

8

Beta strand

233 – 235

3

Beta strand

237 – 246

10

Turn

247 – 250

4

Beta strand

251 – 255

5

Helix

270 – 272

3

Beta strand

278 – 286

9

Beta strand

289 – 299

11

Helix

304 – 306

3

Beta strand

317 – 321

5

Turn

325 – 329

5

Beta strand

330 – 333

4

Beta strand

339 – 348

10

Beta strand

351 – 356

6

Helix

357 – 368

12

Beta strand

380 – 382

3

Beta strand

384 – 389

6

Helix

392 – 401

10

Beta strand

411 – 417

7

Beta strand

419 – 421

3

Helix

422 – 426

5

Beta strand

433 – 437

5

Helix

445 – 454

10

Beta strand

456 – 464

9

Beta strand

467 – 473

7

Beta strand

476 – 478

3

Sequences

	Sequence		Length	Mass (Da)
	Q92743 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: CA20A99480FB2330	FASTA	480	51,287
	10 20 30 40 50 60 MQIPRAALLP LLLLLLAAPA SAQLSRAGRS APLAAGCPDR CEPARCPPQP EHCEGGRARD 70 80 90 100 110 120 ACGCCEVCGA PEGAACGLQE GPCGEGLQCV VPFGVPASAT VRRRAQAGLC VCASSEPVCG 130 140 150 160 170 180 SDANTYANLC QLRAASRRSE RLHRPPVIVL QRGACGQGQE DPNSLRHKYN FIADVVEKIA 190 200 210 220 230 240 PAVVHIELFR KLPFSKREVP VASGSGFIVS EDGLIVTNAH VVTNKHRVKV ELKNGATYEA 250 260 270 280 290 300 KIKDVDEKAD IALIKIDHQG KLPVLLLGRS SELRPGEFVV AIGSPFSLQN TVTTGIVSTT 310 320 330 340 350 360 QRGGKELGLR NSDMDYIQTD AIINYGNSGG PLVNLDGEVI GINTLKVTAG ISFAIPSDKI 370 380 390 400 410 420 KKFLTESHDR QAKGKAITKK KYIGIRMMSL TSSKAKELKD RHRDFPDVIS GAYIIEVIPD 430 440 450 460 470 480 TPAEAGGLKE NDVIISINGQ SVVSANDVSD VIKRESTLNM VVRRGNEDIM ITVIPEEIDP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Primary structure of a putative serine protease specific for IGF-binding proteins." Zumbrunn J., Trueb B. FEBS Lett. 398:187-192(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[2]	"Genomic organization and promoter characterization of the human HTRA (PRSS11) gene." Crowl R.M., Luk D., Milnamow M. Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	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].
[4]	"Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage." Hu S.I., Carozza M., Klein M., Nantermet P., Luk D., Crowl R.M. J. Biol. Chem. 273:34406-34412(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 144-480, PROTEIN SEQUENCE OF 33-44, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF SER-328. Tissue: Cartilage.
[5]	"The serine protease HtrA1 is upregulated in the human placenta during pregnancy." De Luca A., De Falco M., Fedele V., Cobellis L., Mastrogiacomo A., Laforgia V., Tuduce I.L., Campioni M., Giraldi D., Paggi M.G., Baldi A. J. Histochem. Cytochem. 52:885-892(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[6]	"The role of human HtrA1 in arthritic disease." Grau S., Richards P.J., Kerr B., Hughes C., Caterson B., Williams A.S., Junker U., Jones S.A., Clausen T., Ehrmann M. J. Biol. Chem. 281:6124-6129(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[7]	"HTRA1 promoter polymorphism in wet age-related macular degeneration." Dewan A., Liu M., Hartman S., Zhang S.S.-M., Liu D.T.L., Zhao C., Tam P.O.S., Chan W.M., Lam D.S.C., Snyder M., Barnstable C., Pang C.P., Hoh J. Science 314:989-992(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO ARMD7.
[8]	"A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration." Yang Z., Camp N.J., Sun H., Tong Z., Gibbs D., Cameron D.J., Chen H., Zhao Y., Pearson E., Li X., Chien J., DeWan A., Harmon J., Bernstein P.S., Shridhar V., Zabriskie N.A., Hoh J., Howes K., Zhang K. Science 314:992-993(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO ARMD7.
[9]	"The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein." Campioni M., Severino A., Manente L., Tuduce I.L., Toldo S., Caraglia M., Crispi S., Ehrmann M., He X., Maguire J., De Falco M., De Luca A., Shridhar V., Baldi A. Mol. Cancer Res. 8:1248-1260(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"Solution structure of the PDZ-domain of human protease HTRA 1 precursor." RIKEN structural genomics initiative (RSGI) Submitted (APR-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 367-480.
[11]	"Substrate-induced remodeling of the active site regulates human HTRA1 activity." Truebestein L., Tennstaedt A., Monig T., Krojer T., Canellas F., Kaiser M., Clausen T., Ehrmann M. Nat. Struct. Mol. Biol. 18:386-388(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 158-480, HOMOTRIMERIZATION, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-328.
[12]	"Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease." Hara K., Shiga A., Fukutake T., Nozaki H., Miyashita A., Yokoseki A., Kawata H., Koyama A., Arima K., Takahashi T., Ikeda M., Shiota H., Tamura M., Shimoe Y., Hirayama M., Arisato T., Yanagawa S., Tanaka A. , Nakano I., Ikeda S., Yoshida Y., Yamamoto T., Ikeuchi T., Kuwano R., Nishizawa M., Tsuji S., Onodera O. N. Engl. J. Med. 360:1729-1739(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CARASIL THR-252 AND MET-297, CHARACTERIZATION OF VARIANTS CARASIL THR-252 AND MET-297.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Y07921 mRNA. Translation: CAA69226.1.
AF157623 Genomic DNA. Translation: AAD41525.1.
CH471066 Genomic DNA. Translation: EAW49312.1.
CH471066 Genomic DNA. Translation: EAW49313.1.
AF097709 mRNA. Translation: AAC97211.1.

IPI

IPI00003176.

RefSeq

NP_002766.1. NM_002775.4.

UniGene

Hs.501280.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2JOA	NMR	-	A	380-480	[»]
2YTW	NMR	-	A	370-480	[»]
3NUM	X-ray	2.75	A	158-480	[»]
3NWU	X-ray	3.20	A/B/C	158-375	[»]
3NZI	X-ray	2.75	A	158-480	[»]
3TJN	X-ray	3.00	A/B/D	161-367	[»]
3TJO	X-ray	2.30	A/B/D	161-370	[»]
3TJQ	X-ray	2.00	A	35-156	[»]

ProteinModelPortal

Q92743.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33195N.

IntAct

Q92743. 5 interactions.

MINT

MINT-1198897.

STRING

9606.ENSP00000357980.

Protein family/group databases

MEROPS

S01.277.

PTM databases

PhosphoSite

Q92743.

Polymorphism databases

DMDM

18202620.

Proteomic databases

PaxDb

Q92743.

PeptideAtlas

Q92743.

PRIDE

Q92743.

Protocols and materials databases

DNASU

5654.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000368984; ENSP00000357980; ENSG00000166033.

GeneID

5654.

KEGG

hsa:5654.

UCSC

uc001lgj.2. human.

Organism-specific databases

CTD

5654.

GeneCards

GC10P124221.

HGNC

HGNC:9476. HTRA1.

HPA

HPA036655.

MIM

600142. phenotype.
602194. gene.
610149. phenotype.

neXtProt

NX_Q92743.

Orphanet

279. Age-related macular degeneration.
199354. CARASIL syndrome.

PharmGKB

PA33829.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0265.

HOGENOM

HOG000223641.

HOVERGEN

HBG052044.

InParanoid

Q92743.

KO

K08784.

OMA

GNNTVEL.

OrthoDB

EOG4KH2V3.

PhylomeDB

Q92743.

Gene expression databases

ArrayExpress

Q92743.

Bgee

Q92743.

CleanEx

HS_HTRA1.

Genevestigator

Q92743.

GermOnline

ENSG00000166033. Homo sapiens.

Family and domain databases

InterPro

IPR000867. IGFBP-like.
IPR002350. Kazal_dom.
IPR001478. PDZ.
IPR001940. Peptidase_S1C.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00219. IGFBP. 1 hit.
PF07648. Kazal_2. 1 hit.
PF00595. PDZ. 1 hit.
[Graphical view]

PRINTS

PR00834. PROTEASES2C.

SMART

SM00121. IB. 1 hit.
SM00280. KAZAL. 1 hit.
SM00228. PDZ. 1 hit.
[Graphical view]

SUPFAM

SSF50156. PDZ. 1 hit.
SSF50494. Pept_Ser_Cys. 1 hit.

PROSITE

PS51323. IGFBP_N_2. 1 hit.
PS51465. KAZAL_2. 1 hit.
PS50106. PDZ. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

HTRA1. human.

EvolutionaryTrace

Q92743.

GenomeRNAi

5654.

NextBio

21974.

SOURCE

Search...

Entry information

Entry name

HTRA1_HUMAN

Accession

Primary (citable) accession number: Q92743
Secondary accession number(s): D3DRE4, Q9UNS5

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 26, 2001
Last sequence update:	February 1, 1997
Last modified:	May 1, 2013
This is version 127 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.