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Q92743 (HTRA1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length480 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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. Cytoplasmcytosol. 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

Macular degeneration, age-related, 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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2222 Potential
Chain23 – 480458Serine protease HTRA1
PRO_0000026943

Regions

Domain33 – 10068IGFBP N-terminal
Domain98 – 15760Kazal-like
Domain365 – 467103PDZ
Region204 – 364161Serine protease

Sites

Active site2201Charge relay system Potential
Active site2501Charge relay system Potential
Active site3281Charge relay system
Site1691Involved in trimer stabilization
Site1711Involved in trimer stabilization
Site2781Involved in trimer stabilization

Natural variations

Natural variant2521A → 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 variant2971V → 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

Mutagenesis3281S → A: Loss of activity. Ref.4 Ref.11
Sequence conflict3231I → T in AAC97211. Ref.4

Secondary structure

............................................................................... 480
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q92743 [UniParc].

Last modified February 1, 1997. Version 1.
Checksum: CA20A99480FB2330

FASTA48051,287
        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 

« Hide

References

« Hide '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. expand/collapse author list , 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. expand/collapse author list , 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.

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.
CCDSCCDS7630.1.
RefSeqNP_002766.1. NM_002775.4.
UniGeneHs.501280.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2JOANMR-A380-480[»]
2YTWNMR-A370-480[»]
3NUMX-ray2.75A158-480[»]
3NWUX-ray3.20A/B/C158-375[»]
3NZIX-ray2.75A158-480[»]
3TJNX-ray3.00A/B/D161-367[»]
3TJOX-ray2.30A/B/D161-370[»]
3TJQX-ray2.00A35-156[»]
ProteinModelPortalQ92743.
SMRQ92743. Positions 36-154, 160-370, 380-480.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111635. 6 interactions.
DIPDIP-33195N.
IntActQ92743. 6 interactions.
MINTMINT-1198897.
STRING9606.ENSP00000357980.

Protein family/group databases

MEROPSS01.277.

PTM databases

PhosphoSiteQ92743.

Polymorphism databases

DMDM18202620.

Proteomic databases

PaxDbQ92743.
PeptideAtlasQ92743.
PRIDEQ92743.

Protocols and materials databases

DNASU5654.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000368984; ENSP00000357980; ENSG00000166033.
GeneID5654.
KEGGhsa:5654.
UCSCuc001lgj.2. human.

Organism-specific databases

CTD5654.
GeneCardsGC10P124221.
GeneReviewsHTRA1.
HGNCHGNC:9476. HTRA1.
HPAHPA036655.
MIM600142. phenotype.
602194. gene.
610149. phenotype.
neXtProtNX_Q92743.
Orphanet279. Age-related macular degeneration.
199354. CARASIL.
PharmGKBPA33829.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0265.
HOGENOMHOG000223641.
HOVERGENHBG052044.
InParanoidQ92743.
KOK08784.
OMAQRGACGQ.
OrthoDBEOG7V1FR7.
PhylomeDBQ92743.
TreeFamTF323480.

Gene expression databases

ArrayExpressQ92743.
BgeeQ92743.
CleanExHS_HTRA1.
GenevestigatorQ92743.

Family and domain databases

Gene3D2.30.42.10. 1 hit.
InterProIPR009030. Growth_fac_rcpt_N_dom.
IPR000867. IGFBP-like.
IPR002350. Kazal_dom.
IPR001478. PDZ.
IPR001940. Peptidase_S1C.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]
PfamPF00219. IGFBP. 1 hit.
PF07648. Kazal_2. 1 hit.
PF00595. PDZ. 1 hit.
[Graphical view]
PRINTSPR00834. PROTEASES2C.
SMARTSM00121. IB. 1 hit.
SM00280. KAZAL. 1 hit.
SM00228. PDZ. 1 hit.
[Graphical view]
SUPFAMSSF50156. SSF50156. 1 hit.
SSF50494. SSF50494. 1 hit.
SSF57184. SSF57184. 1 hit.
PROSITEPS51323. IGFBP_N_2. 1 hit.
PS51465. KAZAL_2. 1 hit.
PS50106. PDZ. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSHTRA1. human.
EvolutionaryTraceQ92743.
GeneWikiHTRA1.
GenomeRNAi5654.
NextBio21974.
PROQ92743.
SOURCESearch...

Entry information

Entry nameHTRA1_HUMAN
AccessionPrimary (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: July 9, 2014
This is version 138 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 10

Human chromosome 10: entries, gene names and cross-references to MIM