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Protein

Serine protease HTRA1

Gene

HTRA1

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

Functioni

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.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei169Involved in trimer stabilization1 Publication1
Sitei171Involved in trimer stabilization1 Publication1
Active sitei220Charge relay system1 Publication1
Active sitei250Charge relay system1 Publication1
Sitei278Involved in trimer stabilization1 Publication1
Active sitei328Charge relay system1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionGrowth factor binding, Hydrolase, Protease, Serine protease

Enzyme and pathway databases

BRENDAi3.4.21.108 2681
ReactomeiR-HSA-1474228 Degradation of the extracellular matrix

Protein family/group databases

MEROPSiS01.277

Names & Taxonomyi

Protein namesi
Recommended name:
Serine protease HTRA1 (EC:3.4.21.-)
Alternative name(s):
High-temperature requirement A serine peptidase 1
L56
Serine protease 11
Gene namesi
Name:HTRA1
Synonyms:HTRA, PRSS11
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000166033.11
HGNCiHGNC:9476 HTRA1
MIMi602194 gene
neXtProtiNX_Q92743

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Macular degeneration, age-related, 7 (ARMD7)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:610149
Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy (CARASIL)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:600142
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063148252A → T in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. 1 PublicationCorresponds to variant dbSNP:rs113993968EnsemblClinVar.1
Natural variantiVAR_063149297V → M in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. 1 PublicationCorresponds to variant dbSNP:rs113993969EnsemblClinVar.1
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke.
See also OMIM:616779
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_076373121S → R in CADASIL2. 1 Publication1
Natural variantiVAR_076374123A → S in CADASIL2. 1 Publication1
Natural variantiVAR_076375133R → G in CADASIL2. 1 Publication1
Natural variantiVAR_076376166R → L in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs864622781EnsemblClinVar.1
Natural variantiVAR_076377173A → P in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs781563777EnsemblClinVar.1
Natural variantiVAR_076378284S → G in CADASIL2; partial loss of proteolytic activity. 1 Publication1
Natural variantiVAR_076379284S → R in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs864622782EnsemblClinVar.1
Natural variantiVAR_076380285P → Q in CADASIL2; loss of proteolytic activity. 1 Publication1
Natural variantiVAR_076381286F → V in CADASIL2; loss of proteolytic activity. 1 Publication1
Natural variantiVAR_076382450D → H in CADASIL2; unknown pathological significance; small decrease, if any, in proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs772225907Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi328S → A: Loss of activity. 2 Publications1

Keywords - Diseasei

Age-related macular degeneration, Disease mutation

Organism-specific databases

DisGeNETi5654
GeneReviewsiHTRA1
MalaCardsiHTRA1
MIMi600142 phenotype
610149 phenotype
616779 phenotype
OpenTargetsiENSG00000166033
Orphaneti279 Age-related macular degeneration
199354 CARASIL
PharmGKBiPA33829

Polymorphism and mutation databases

BioMutaiHTRA1
DMDMi18202620

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 22Sequence analysisAdd BLAST22
ChainiPRO_000002694323 – 480Serine protease HTRA1Add BLAST458

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi110 ↔ 130PROSITE-ProRule annotation
Disulfide bondi119 ↔ 155PROSITE-ProRule annotation

Keywords - PTMi

Disulfide bond

Proteomic databases

EPDiQ92743
PaxDbiQ92743
PeptideAtlasiQ92743
PRIDEiQ92743

PTM databases

iPTMnetiQ92743
PhosphoSitePlusiQ92743

Expressioni

Tissue specificityi

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).3 Publications

Developmental stagei

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).1 Publication

Gene expression databases

BgeeiENSG00000166033
CleanExiHS_HTRA1
ExpressionAtlasiQ92743 baseline and differential
GenevisibleiQ92743 HS

Organism-specific databases

HPAiHPA036655

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • insulin-like growth factor binding Source: InterPro

Protein-protein interaction databases

BioGridi111635, 20 interactors
DIPiDIP-33195N
IntActiQ92743, 9 interactors
MINTiQ92743
STRINGi9606.ENSP00000357980

Structurei

Secondary structure

1480
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi43 – 45Combined sources3
Beta strandi57 – 59Combined sources3
Beta strandi65 – 68Combined sources4
Beta strandi74 – 77Combined sources4
Beta strandi87 – 90Combined sources4
Beta strandi108 – 113Combined sources6
Beta strandi118 – 123Combined sources6
Beta strandi125 – 128Combined sources4
Helixi129 – 141Combined sources13
Helixi165 – 168Combined sources4
Helixi171 – 179Combined sources9
Helixi180 – 182Combined sources3
Beta strandi183 – 191Combined sources9
Beta strandi193 – 196Combined sources4
Beta strandi198 – 208Combined sources11
Turni211 – 213Combined sources3
Beta strandi214 – 218Combined sources5
Turni219 – 221Combined sources3
Beta strandi224 – 231Combined sources8
Beta strandi233 – 235Combined sources3
Beta strandi237 – 246Combined sources10
Turni247 – 250Combined sources4
Beta strandi251 – 255Combined sources5
Helixi270 – 272Combined sources3
Beta strandi278 – 286Combined sources9
Beta strandi289 – 299Combined sources11
Beta strandi301 – 303Combined sources3
Helixi304 – 306Combined sources3
Beta strandi317 – 321Combined sources5
Turni325 – 329Combined sources5
Beta strandi330 – 333Combined sources4
Beta strandi339 – 348Combined sources10
Beta strandi351 – 356Combined sources6
Helixi357 – 368Combined sources12
Beta strandi380 – 382Combined sources3
Beta strandi384 – 389Combined sources6
Helixi392 – 401Combined sources10
Beta strandi411 – 417Combined sources7
Beta strandi419 – 421Combined sources3
Helixi422 – 426Combined sources5
Beta strandi433 – 437Combined sources5
Helixi445 – 454Combined sources10
Beta strandi456 – 464Combined sources9
Beta strandi467 – 473Combined sources7
Beta strandi476 – 478Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
ProteinModelPortaliQ92743
SMRiQ92743
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ92743

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini33 – 100IGFBP N-terminalPROSITE-ProRule annotationAdd BLAST68
Domaini98 – 157Kazal-likePROSITE-ProRule annotationAdd BLAST60
Domaini365 – 467PDZPROSITE-ProRule annotationAdd BLAST103

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni204 – 364Serine proteaseAdd BLAST161

Domaini

The IGFBP N-terminal domain mediates interaction with TSC2 substrate.

Sequence similaritiesi

Belongs to the peptidase S1C family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG1320 Eukaryota
COG0265 LUCA
GeneTreeiENSGT00510000046315
HOGENOMiHOG000223641
HOVERGENiHBG052044
InParanoidiQ92743
KOiK08784
OMAiTYANLCQ
OrthoDBiEOG091G0LXR
PhylomeDBiQ92743
TreeFamiTF323480

Family and domain databases

InterProiView protein in InterPro
IPR009030 Growth_fac_rcpt_cys_sf
IPR000867 IGFBP-like
IPR002350 Kazal_dom
IPR036058 Kazal_dom_sf
IPR001478 PDZ
IPR036034 PDZ_sf
IPR009003 Peptidase_S1_PA
IPR001940 Peptidase_S1C
PfamiView protein in Pfam
PF00219 IGFBP, 1 hit
PF07648 Kazal_2, 1 hit
PF00595 PDZ, 1 hit
PRINTSiPR00834 PROTEASES2C
SMARTiView protein in SMART
SM00121 IB, 1 hit
SM00280 KAZAL, 1 hit
SM00228 PDZ, 1 hit
SUPFAMiSSF100895 SSF100895, 1 hit
SSF50156 SSF50156, 1 hit
SSF50494 SSF50494, 1 hit
SSF57184 SSF57184, 1 hit
PROSITEiView protein in PROSITE
PS51323 IGFBP_N_2, 1 hit
PS51465 KAZAL_2, 1 hit
PS50106 PDZ, 1 hit

Sequencei

Sequence statusi: Complete.

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

Q92743-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQIPRAALLP LLLLLLAAPA SAQLSRAGRS APLAAGCPDR CEPARCPPQP
60 70 80 90 100
EHCEGGRARD ACGCCEVCGA PEGAACGLQE GPCGEGLQCV VPFGVPASAT
110 120 130 140 150
VRRRAQAGLC VCASSEPVCG SDANTYANLC QLRAASRRSE RLHRPPVIVL
160 170 180 190 200
QRGACGQGQE DPNSLRHKYN FIADVVEKIA PAVVHIELFR KLPFSKREVP
210 220 230 240 250
VASGSGFIVS EDGLIVTNAH VVTNKHRVKV ELKNGATYEA KIKDVDEKAD
260 270 280 290 300
IALIKIDHQG KLPVLLLGRS SELRPGEFVV AIGSPFSLQN TVTTGIVSTT
310 320 330 340 350
QRGGKELGLR NSDMDYIQTD AIINYGNSGG PLVNLDGEVI GINTLKVTAG
360 370 380 390 400
ISFAIPSDKI KKFLTESHDR QAKGKAITKK KYIGIRMMSL TSSKAKELKD
410 420 430 440 450
RHRDFPDVIS GAYIIEVIPD TPAEAGGLKE NDVIISINGQ SVVSANDVSD
460 470 480
VIKRESTLNM VVRRGNEDIM ITVIPEEIDP
Length:480
Mass (Da):51,287
Last modified:February 1, 1997 - v1
Checksum:iCA20A99480FB2330
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti323I → T in AAC97211 (PubMed:9852107).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07637120A → V1 PublicationCorresponds to variant dbSNP:rs369149111EnsemblClinVar.1
Natural variantiVAR_07637251E → G1 Publication1
Natural variantiVAR_076373121S → R in CADASIL2. 1 Publication1
Natural variantiVAR_076374123A → S in CADASIL2. 1 Publication1
Natural variantiVAR_076375133R → G in CADASIL2. 1 Publication1
Natural variantiVAR_076376166R → L in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs864622781EnsemblClinVar.1
Natural variantiVAR_076377173A → P in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs781563777EnsemblClinVar.1
Natural variantiVAR_063148252A → T in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. 1 PublicationCorresponds to variant dbSNP:rs113993968EnsemblClinVar.1
Natural variantiVAR_076378284S → G in CADASIL2; partial loss of proteolytic activity. 1 Publication1
Natural variantiVAR_076379284S → R in CADASIL2; loss of proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs864622782EnsemblClinVar.1
Natural variantiVAR_076380285P → Q in CADASIL2; loss of proteolytic activity. 1 Publication1
Natural variantiVAR_076381286F → V in CADASIL2; loss of proteolytic activity. 1 Publication1
Natural variantiVAR_063149297V → M in CARASIL; has 21 to 50% normal protease activity; is unable to suppress TGF-beta activity. 1 PublicationCorresponds to variant dbSNP:rs113993969EnsemblClinVar.1
Natural variantiVAR_076382450D → H in CADASIL2; unknown pathological significance; small decrease, if any, in proteolytic activity. 1 PublicationCorresponds to variant dbSNP:rs772225907Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS7630.1
RefSeqiNP_002766.1, NM_002775.4
UniGeneiHs.501280

Genome annotation databases

EnsembliENST00000368984; ENSP00000357980; ENSG00000166033
GeneIDi5654
KEGGihsa:5654
UCSCiuc001lgj.2 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHTRA1_HUMAN
AccessioniPrimary (citable) accession number: Q92743
Secondary accession number(s): D3DRE4, Q9UNS5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: February 1, 1997
Last modified: May 23, 2018
This is version 171 of the entry and version 1 of the sequence. See 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 10
    Human chromosome 10: 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

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