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Protein

Serine protease HTRA3

Gene

HTRA3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine protease that cleaves beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans such as decorin/DCN, biglycan/BGN and fibronectin/FN1. Inhibits signaling mediated by TGF-beta family proteins possibly indirectly by degradation of these ECM proteoglycans (By similarity). May act as a tumor suppressor. Negatively regulates, in vitro, trophoblast invasion during placental development and may be involved in the development of the placenta in vivo. May also have a role in ovarian development, granulosa cell differentiation and luteinization.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei191 – 1911Charge relay systemSequence Analysis
Active sitei227 – 2271Charge relay systemSequence Analysis
Active sitei305 – 3051Charge relay system

GO - Molecular functioni

  • endopeptidase activity Source: BHF-UCL
  • serine-type endopeptidase activity Source: InterPro
  • serine-type peptidase activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Protein family/group databases

MEROPSiS01.284.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine protease HTRA3 (EC:3.4.21.-)
Alternative name(s):
High-temperature requirement factor A3
Pregnancy-related serine protease
Gene namesi
Name:HTRA3
Synonyms:PRSP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 4

Organism-specific databases

HGNCiHGNC:30406. HTRA3.

Subcellular locationi

  • Secreted 1 Publication

  • Note: Secretion increased during decidualization of endometrial stromal cells.

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi305 – 3051S → A: Abolishes protease activity. Stabilizes the protein. 1 Publication

Organism-specific databases

PharmGKBiPA134908281.

Polymorphism and mutation databases

BioMutaiHTRA3.
DMDMi21542412.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1717Sequence AnalysisAdd
BLAST
Chaini18 – 453436Serine protease HTRA3PRO_0000026949Add
BLAST

Proteomic databases

MaxQBiP83110.
PaxDbiP83110.
PRIDEiP83110.

PTM databases

PhosphoSiteiP83110.

Expressioni

Tissue specificityi

Widely expressed, with highest levels in both adult and fetal heart, ovary, uterus placenta, and bladder. In the endometrium, expressed in epithelial glands and the stroma. Also present in leukocytes. Isoform 1 is predominant in heart and skeletal muscle, whereas isoform 2 is predominant in placenta and kidney.3 Publications

Inductioni

Down-regulated in ovarian and endometrial cancers (EC). Decrease of 3.2-fold in endometrial cancer.2 Publications

Gene expression databases

BgeeiP83110.
CleanExiHS_HTRA3.
GenevisibleiP83110. HS.

Organism-specific databases

HPAiHPA021187.

Interactioni

Subunit structurei

Homotrimer (By similarity). Interacts with TGFB1; the interaction inhibits TGFB-mediated signaling. Interacts with BMP4; the interaction inhibits BMP4-mediated signaling. Interacts with TGFB2 and GDF5 (By similarity). Interacts with MYH9.By similarity2 Publications

Protein-protein interaction databases

BioGridi125099. 2 interactions.
IntActiP83110. 2 interactions.
MINTiMINT-4786544.
STRINGi9606.ENSP00000303766.

Structurei

Secondary structure

1
453
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi136 – 1394Combined sources
Helixi142 – 1509Combined sources
Helixi151 – 1533Combined sources
Beta strandi154 – 1618Combined sources
Beta strandi166 – 1683Combined sources
Beta strandi171 – 18111Combined sources
Turni182 – 1843Combined sources
Beta strandi185 – 1884Combined sources
Turni190 – 1934Combined sources
Beta strandi203 – 2086Combined sources
Beta strandi214 – 22310Combined sources
Turni224 – 2274Combined sources
Beta strandi228 – 2336Combined sources
Helixi247 – 2493Combined sources
Beta strandi255 – 2606Combined sources
Beta strandi268 – 2747Combined sources
Beta strandi294 – 2985Combined sources
Turni302 – 3065Combined sources
Beta strandi307 – 3104Combined sources
Beta strandi316 – 32510Combined sources
Beta strandi328 – 3336Combined sources
Helixi334 – 3429Combined sources
Beta strandi354 – 3563Combined sources
Beta strandi359 – 3635Combined sources
Helixi366 – 37510Combined sources
Beta strandi384 – 3918Combined sources
Helixi396 – 4005Combined sources
Beta strandi407 – 4115Combined sources
Helixi419 – 42810Combined sources
Beta strandi430 – 4389Combined sources
Beta strandi441 – 4477Combined sources
Beta strandi450 – 4523Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2P3WX-ray1.70A/B354-453[»]
4RI0X-ray3.27A/B/C130-453[»]
ProteinModelPortaliP83110.
SMRiP83110. Positions 25-125, 135-453.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP83110.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini21 – 7757IGFBP N-terminalPROSITE-ProRule annotationAdd
BLAST
Domaini64 – 12865Kazal-likePROSITE-ProRule annotationAdd
BLAST
Domaini359 – 44486PDZPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni175 – 340166Serine proteaseAdd
BLAST

Sequence similaritiesi

Belongs to the peptidase S1C family.Curated
Contains 1 IGFBP N-terminal domain.PROSITE-ProRule annotation
Contains 1 Kazal-like domain.PROSITE-ProRule annotation
Contains 1 PDZ (DHR) domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiCOG0265.
GeneTreeiENSGT00510000046315.
HOGENOMiHOG000223641.
HOVERGENiHBG052044.
InParanoidiP83110.
KOiK08785.
OMAiCRCRWTH.
OrthoDBiEOG7V1FR7.
PhylomeDBiP83110.
TreeFamiTF323480.

Family and domain databases

Gene3Di2.30.42.10. 1 hit.
InterProiIPR009030. Growth_fac_rcpt_N_dom.
IPR000867. IGFBP-like.
IPR002350. Kazal_dom.
IPR001478. PDZ.
IPR001940. Peptidase_S1C.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]
PfamiPF07648. Kazal_2. 1 hit.
PF13180. PDZ_2. 1 hit.
[Graphical view]
PRINTSiPR00834. PROTEASES2C.
SMARTiSM00121. IB. 1 hit.
SM00280. KAZAL. 1 hit.
SM00228. PDZ. 1 hit.
[Graphical view]
SUPFAMiSSF50156. SSF50156. 1 hit.
SSF50494. SSF50494. 1 hit.
SSF57184. SSF57184. 1 hit.
PROSITEiPS51323. IGFBP_N_2. 1 hit.
PS51465. KAZAL_2. 1 hit.
PS50106. PDZ. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P83110-1) [UniParc]FASTAAdd to basket

Also known as: Long, pL

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.

« Hide

        10         20         30         40         50
MQARALLLAA LAALALAREP PAAPCPARCD VSRCPSPRCP GGYVPDLCNC
60 70 80 90 100
CLVCAASEGE PCGGPLDSPC GESLECVRGL CRCRWSHAVC GTDGHTYANV
110 120 130 140 150
CALQAASRRA LQLSGTPVRQ LQKGACPLGL HQLSSPRYKF NFIADVVEKI
160 170 180 190 200
APAVVHIELF LRHPLFGRNV PLSSGSGFIM SEAGLIITNA HVVSSNSAAP
210 220 230 240 250
GRQQLKVQLQ NGDSYEATIK DIDKKSDIAT IKIHPKKKLP VLLLGHSADL
260 270 280 290 300
RPGEFVVAIG SPFALQNTVT TGIVSTAQRE GRELGLRDSD MDYIQTDAII
310 320 330 340 350
NYGNSGGPLV NLDGEVIGIN TLKVTAGISF AIPSDRITRF LTEFQDKQIK
360 370 380 390 400
DWKKRFIGIR MRTITPSLVD ELKASNPDFP EVSSGIYVQE VAPNSPSQRG
410 420 430 440 450
GIQDGDIIVK VNGRPLVDSS ELQEAVLTES PLLLEVRRGN DDLLFSIAPE

VVM
Length:453
Mass (Da):48,608
Last modified:June 20, 2002 - v2
Checksum:i3046FCDA1AB24FA6
GO
Isoform 2 (identifier: P83110-2) [UniParc]FASTAAdd to basket

Also known as: Short, pS

The sequence of this isoform differs from the canonical sequence as follows:
     351-357: DWKKRFI → APSLAVH
     358-453: Missing.

Show »
Length:357
Mass (Da):37,940
Checksum:i8A62D2B9823BC420
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei351 – 3577DWKKRFI → APSLAVH in isoform 2. 1 PublicationVSP_012570
Alternative sequencei358 – 45396Missing in isoform 2. 1 PublicationVSP_012571Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY280665 mRNA. Translation: AAP42282.1.
AY280666 mRNA. Translation: AAP42283.1.
AY040094 mRNA. Translation: AAK71475.2.
AC113611 Genomic DNA. No translation available.
BC034390 mRNA. Translation: AAH34390.1.
BC035717 mRNA. Translation: AAH35717.1.
CCDSiCCDS3400.1. [P83110-1]
CCDS75105.1. [P83110-2]
RefSeqiNP_001284488.1. NM_001297559.1. [P83110-2]
NP_444272.1. NM_053044.4. [P83110-1]
UniGeneiHs.479119.

Genome annotation databases

EnsembliENST00000307358; ENSP00000303766; ENSG00000170801.
ENST00000382512; ENSP00000371952; ENSG00000170801. [P83110-2]
GeneIDi94031.
KEGGihsa:94031.
UCSCiuc003gkz.3. human. [P83110-2]
uc003gla.3. human. [P83110-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY280665 mRNA. Translation: AAP42282.1.
AY280666 mRNA. Translation: AAP42283.1.
AY040094 mRNA. Translation: AAK71475.2.
AC113611 Genomic DNA. No translation available.
BC034390 mRNA. Translation: AAH34390.1.
BC035717 mRNA. Translation: AAH35717.1.
CCDSiCCDS3400.1. [P83110-1]
CCDS75105.1. [P83110-2]
RefSeqiNP_001284488.1. NM_001297559.1. [P83110-2]
NP_444272.1. NM_053044.4. [P83110-1]
UniGeneiHs.479119.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2P3WX-ray1.70A/B354-453[»]
4RI0X-ray3.27A/B/C130-453[»]
ProteinModelPortaliP83110.
SMRiP83110. Positions 25-125, 135-453.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi125099. 2 interactions.
IntActiP83110. 2 interactions.
MINTiMINT-4786544.
STRINGi9606.ENSP00000303766.

Protein family/group databases

MEROPSiS01.284.

PTM databases

PhosphoSiteiP83110.

Polymorphism and mutation databases

BioMutaiHTRA3.
DMDMi21542412.

Proteomic databases

MaxQBiP83110.
PaxDbiP83110.
PRIDEiP83110.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000307358; ENSP00000303766; ENSG00000170801.
ENST00000382512; ENSP00000371952; ENSG00000170801. [P83110-2]
GeneIDi94031.
KEGGihsa:94031.
UCSCiuc003gkz.3. human. [P83110-2]
uc003gla.3. human. [P83110-1]

Organism-specific databases

CTDi94031.
GeneCardsiGC04P008271.
HGNCiHGNC:30406. HTRA3.
HPAiHPA021187.
MIMi608785. gene.
neXtProtiNX_P83110.
PharmGKBiPA134908281.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0265.
GeneTreeiENSGT00510000046315.
HOGENOMiHOG000223641.
HOVERGENiHBG052044.
InParanoidiP83110.
KOiK08785.
OMAiCRCRWTH.
OrthoDBiEOG7V1FR7.
PhylomeDBiP83110.
TreeFamiTF323480.

Miscellaneous databases

EvolutionaryTraceiP83110.
GenomeRNAii94031.
NextBioi78335.
PROiP83110.
SOURCEiSearch...

Gene expression databases

BgeeiP83110.
CleanExiHS_HTRA3.
GenevisibleiP83110. HS.

Family and domain databases

Gene3Di2.30.42.10. 1 hit.
InterProiIPR009030. Growth_fac_rcpt_N_dom.
IPR000867. IGFBP-like.
IPR002350. Kazal_dom.
IPR001478. PDZ.
IPR001940. Peptidase_S1C.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]
PfamiPF07648. Kazal_2. 1 hit.
PF13180. PDZ_2. 1 hit.
[Graphical view]
PRINTSiPR00834. PROTEASES2C.
SMARTiSM00121. IB. 1 hit.
SM00280. KAZAL. 1 hit.
SM00228. PDZ. 1 hit.
[Graphical view]
SUPFAMiSSF50156. SSF50156. 1 hit.
SSF50494. SSF50494. 1 hit.
SSF57184. SSF57184. 1 hit.
PROSITEiPS51323. IGFBP_N_2. 1 hit.
PS51465. KAZAL_2. 1 hit.
PS50106. PDZ. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2."
    Nie G.-Y., Hampton A., Li Y., Findlay J.K., Salamonsen L.A.
    Biochem. J. 371:39-48(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY.
    Tissue: Heart.
  2. Southan C., Punia P.K.
    Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  3. "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: Brain and Ovary.
  4. "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].
  5. "Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer."
    Bowden M.A., Di Nezza-Cossens L.A., Jobling T., Salamonsen L.A., Nie G.
    Gynecol. Oncol. 103:253-260(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION, TISSUE SPECIFICITY.
  6. "Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer."
    Narkiewicz J., Lapinska-Szumczyk S., Zurawa-Janicka D., Skorko-Glonek J., Emerich J., Lipinska B.
    Oncol. Rep. 21:1529-1537(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  7. "Decidual HtrA3 negatively regulates trophoblast invasion during human placentation."
    Singh H., Endo Y., Nie G.
    Hum. Reprod. 26:748-757(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION, POSSIBLE FUNCTION.
  8. "Application of the wheat-germ cell-free translation system to produce high temperature requirement A3 (HtrA3) proteases."
    Singh H., Makino S., Endo Y., Li Y., Stephens A.N., Nie G.
    BioTechniques 52:23-28(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH MYH9, ENZYME ACTIVITY, MUTAGENESIS OF SER-305.
  9. "Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3."
    Runyon S.T., Zhang Y., Appleton B.A., Sazinsky S.L., Wu P., Pan B., Wiesmann C., Skelton N.J., Sidhu S.S.
    Protein Sci. 16:2454-2471(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 354-453 IN COMPLEX WITH SYNTHETIC PEPTIDES.

Entry informationi

Entry nameiHTRA3_HUMAN
AccessioniPrimary (citable) accession number: P83110
Secondary accession number(s): Q7Z7A2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: June 20, 2002
Last modified: July 22, 2015
This is version 128 of the entry and version 2 of the sequence. [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, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Peptidase families
    Classification of peptidase families and list of entries
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.