HTRA3_HUMAN
ID HTRA3_HUMAN Reviewed; 453 AA.
AC P83110; Q7Z7A2;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2002, sequence version 2.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Serine protease HTRA3;
DE EC=3.4.21.-;
DE AltName: Full=High-temperature requirement factor A3;
DE AltName: Full=Pregnancy-related serine protease;
DE Flags: Precursor;
GN Name=HTRA3; Synonyms=PRSP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RC TISSUE=Heart;
RX PubMed=12513693; DOI=10.1042/bj20021569;
RA Nie G.-Y., Hampton A., Li Y., Findlay J.K., Salamonsen L.A.;
RT "Identification and cloning of two isoforms of human high-temperature
RT requirement factor A3 (HtrA3), characterization of its genomic structure
RT and comparison of its tissue distribution with HtrA1 and HtrA2.";
RL Biochem. J. 371:39-48(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Southan C., Punia P.K.;
RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=16650464; DOI=10.1016/j.ygyno.2006.03.006;
RA Bowden M.A., Di Nezza-Cossens L.A., Jobling T., Salamonsen L.A., Nie G.;
RT "Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades
RT of human endometrial cancer.";
RL Gynecol. Oncol. 103:253-260(2006).
RN [6]
RP INDUCTION.
RX PubMed=19424634; DOI=10.3892/or_00000385;
RA Narkiewicz J., Lapinska-Szumczyk S., Zurawa-Janicka D., Skorko-Glonek J.,
RA Emerich J., Lipinska B.;
RT "Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary
RT endometrial cancer.";
RL Oncol. Rep. 21:1529-1537(2009).
RN [7]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND POSSIBLE FUNCTION.
RX PubMed=21321049; DOI=10.1093/humrep/der019;
RA Singh H., Endo Y., Nie G.;
RT "Decidual HtrA3 negatively regulates trophoblast invasion during human
RT placentation.";
RL Hum. Reprod. 26:748-757(2011).
RN [8]
RP INTERACTION WITH MYH9, MUTAGENESIS OF SER-305, ACTIVE SITE, AND FUNCTION.
RX PubMed=22229724; DOI=10.2144/000113798;
RA Singh H., Makino S., Endo Y., Li Y., Stephens A.N., Nie G.;
RT "Application of the wheat-germ cell-free translation system to produce high
RT temperature requirement A3 (HtrA3) proteases.";
RL BioTechniques 52:23-28(2012).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 354-453 IN COMPLEX WITH SYNTHETIC
RP PEPTIDES.
RX PubMed=17962403; DOI=10.1110/ps.073049407;
RA Runyon S.T., Zhang Y., Appleton B.A., Sazinsky S.L., Wu P., Pan B.,
RA Wiesmann C., Skelton N.J., Sidhu S.S.;
RT "Structural and functional analysis of the PDZ domains of human HtrA1 and
RT HtrA3.";
RL Protein Sci. 16:2454-2471(2007).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (3.27 ANGSTROMS) OF 130-453, SUBUNIT, AND ACTIVE
RP SITE.
RX PubMed=26110759; DOI=10.1371/journal.pone.0131142;
RA Glaza P., Osipiuk J., Wenta T., Zurawa-Janicka D., Jarzab M., Lesner A.,
RA Banecki B., Skorko-Glonek J., Joachimiak A., Lipinska B.;
RT "Structural and functional analysis of human HtrA3 protease and its
RT subdomains.";
RL PLoS ONE 10:E0131142-E0131142(2015).
CC -!- FUNCTION: Serine protease that cleaves beta-casein/CSN2 as well as
CC several extracellular matrix (ECM) proteoglycans such as decorin/DCN,
CC biglycan/BGN and fibronectin/FN1. Inhibits signaling mediated by TGF-
CC beta family proteins possibly indirectly by degradation of these ECM
CC proteoglycans (By similarity). May act as a tumor suppressor.
CC Negatively regulates, in vitro, trophoblast invasion during placental
CC development and may be involved in the development of the placenta in
CC vivo. May also have a role in ovarian development, granulosa cell
CC differentiation and luteinization (PubMed:21321049, PubMed:22229724).
CC {ECO:0000250|UniProtKB:Q9D236, ECO:0000269|PubMed:21321049,
CC ECO:0000269|PubMed:22229724}.
CC -!- SUBUNIT: Homotrimer (PubMed:26110759). Interacts with TGFB1; the
CC interaction inhibits TGFB-mediated signaling. Interacts with BMP4; the
CC interaction inhibits BMP4-mediated signaling. Interacts with TGFB2 and
CC GDF5 (By similarity). Interacts with MYH9.
CC {ECO:0000250|UniProtKB:Q9D236, ECO:0000269|PubMed:17962403,
CC ECO:0000269|PubMed:22229724, ECO:0000269|PubMed:26110759}.
CC -!- INTERACTION:
CC P83110; P60709: ACTB; NbExp=5; IntAct=EBI-2867394, EBI-353944;
CC P83110; P83110: HTRA3; NbExp=3; IntAct=EBI-2867394, EBI-2867394;
CC P83110; P83105: HTRA4; NbExp=5; IntAct=EBI-2867394, EBI-21776319;
CC P83110; P17987: TCP1; NbExp=5; IntAct=EBI-2867394, EBI-356553;
CC P83110; P98170: XIAP; NbExp=8; IntAct=EBI-2867394, EBI-517127;
CC P83110; P02666: CSN2; Xeno; NbExp=8; IntAct=EBI-2867394, EBI-5260183;
CC P83110-1; P83110-1: HTRA3; NbExp=2; IntAct=EBI-25469082, EBI-25469082;
CC P83110-1; P17987: TCP1; NbExp=6; IntAct=EBI-25469082, EBI-356553;
CC P83110-1; P08670: VIM; NbExp=4; IntAct=EBI-25469082, EBI-353844;
CC P83110-1; P98170: XIAP; NbExp=7; IntAct=EBI-25469082, EBI-517127;
CC P83110-2; P17987: TCP1; NbExp=7; IntAct=EBI-22017714, EBI-356553;
CC P83110-2; P08670: VIM; NbExp=5; IntAct=EBI-22017714, EBI-353844;
CC P83110-2; P98170: XIAP; NbExp=6; IntAct=EBI-22017714, EBI-517127;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:21321049}.
CC Note=Secretion increased during decidualization of endometrial stromal
CC cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long, pL;
CC IsoId=P83110-1; Sequence=Displayed;
CC Name=2; Synonyms=Short, pS;
CC IsoId=P83110-2; Sequence=VSP_012570, VSP_012571;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in both adult
CC and fetal heart, ovary, uterus placenta, and bladder. In the
CC endometrium, expressed in epithelial glands and the stroma. Also
CC present in leukocytes. Isoform 1 is predominant in heart and skeletal
CC muscle, whereas isoform 2 is predominant in placenta and kidney.
CC {ECO:0000269|PubMed:12513693, ECO:0000269|PubMed:16650464,
CC ECO:0000269|PubMed:21321049}.
CC -!- INDUCTION: Down-regulated in ovarian and endometrial cancers (EC).
CC Decrease of 3.2-fold in endometrial cancer.
CC {ECO:0000269|PubMed:16650464, ECO:0000269|PubMed:19424634}.
CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HTRA3ID45757ch4p16.html";
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DR EMBL; AY280665; AAP42282.1; -; mRNA.
DR EMBL; AY280666; AAP42283.1; -; mRNA.
DR EMBL; AY040094; AAK71475.2; -; mRNA.
DR EMBL; AC113611; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC034390; AAH34390.1; -; mRNA.
DR EMBL; BC035717; AAH35717.1; -; mRNA.
DR CCDS; CCDS3400.1; -. [P83110-1]
DR CCDS; CCDS75105.1; -. [P83110-2]
DR RefSeq; NP_001284488.1; NM_001297559.1. [P83110-2]
DR RefSeq; NP_444272.1; NM_053044.4. [P83110-1]
DR PDB; 2P3W; X-ray; 1.70 A; A/B=354-453.
DR PDB; 4RI0; X-ray; 3.27 A; A/B/C=130-453.
DR PDBsum; 2P3W; -.
DR PDBsum; 4RI0; -.
DR AlphaFoldDB; P83110; -.
DR SMR; P83110; -.
DR BioGRID; 125099; 30.
DR IntAct; P83110; 24.
DR STRING; 9606.ENSP00000303766; -.
DR MEROPS; S01.284; -.
DR iPTMnet; P83110; -.
DR PhosphoSitePlus; P83110; -.
DR BioMuta; HTRA3; -.
DR DMDM; 21542412; -.
DR jPOST; P83110; -.
DR MassIVE; P83110; -.
DR MaxQB; P83110; -.
DR PaxDb; P83110; -.
DR PeptideAtlas; P83110; -.
DR PRIDE; P83110; -.
DR ProteomicsDB; 57731; -. [P83110-1]
DR ProteomicsDB; 57732; -. [P83110-2]
DR Antibodypedia; 9597; 115 antibodies from 26 providers.
DR DNASU; 94031; -.
DR Ensembl; ENST00000307358.7; ENSP00000303766.2; ENSG00000170801.10. [P83110-1]
DR Ensembl; ENST00000382512.3; ENSP00000371952.3; ENSG00000170801.10. [P83110-2]
DR GeneID; 94031; -.
DR KEGG; hsa:94031; -.
DR MANE-Select; ENST00000307358.7; ENSP00000303766.2; NM_053044.5; NP_444272.1.
DR UCSC; uc003gkz.4; human. [P83110-1]
DR CTD; 94031; -.
DR DisGeNET; 94031; -.
DR GeneCards; HTRA3; -.
DR HGNC; HGNC:30406; HTRA3.
DR HPA; ENSG00000170801; Tissue enhanced (heart).
DR MIM; 608785; gene.
DR neXtProt; NX_P83110; -.
DR OpenTargets; ENSG00000170801; -.
DR PharmGKB; PA134908281; -.
DR VEuPathDB; HostDB:ENSG00000170801; -.
DR eggNOG; ENOG502QT3F; Eukaryota.
DR GeneTree; ENSGT00940000159570; -.
DR HOGENOM; CLU_020120_6_2_1; -.
DR InParanoid; P83110; -.
DR OMA; NDTDAFP; -.
DR OrthoDB; 630723at2759; -.
DR PhylomeDB; P83110; -.
DR TreeFam; TF323480; -.
DR BRENDA; 3.4.21.108; 2681.
DR PathwayCommons; P83110; -.
DR SignaLink; P83110; -.
DR BioGRID-ORCS; 94031; 14 hits in 1070 CRISPR screens.
DR EvolutionaryTrace; P83110; -.
DR GenomeRNAi; 94031; -.
DR Pharos; P83110; Tbio.
DR PRO; PR:P83110; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P83110; protein.
DR Bgee; ENSG00000170801; Expressed in apex of heart and 161 other tissues.
DR Genevisible; P83110; HS.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0004175; F:endopeptidase activity; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0008236; F:serine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR Gene3D; 2.30.42.10; -; 1.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR000867; IGFBP-like.
DR InterPro; IPR002350; Kazal_dom.
DR InterPro; IPR036058; Kazal_dom_sf.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR001940; Peptidase_S1C.
DR Pfam; PF00219; IGFBP; 1.
DR Pfam; PF07648; Kazal_2; 1.
DR Pfam; PF13180; PDZ_2; 1.
DR PRINTS; PR00834; PROTEASES2C.
DR SMART; SM00121; IB; 1.
DR SMART; SM00280; KAZAL; 1.
DR SMART; SM00228; PDZ; 1.
DR SUPFAM; SSF100895; SSF100895; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS51323; IGFBP_N_2; 1.
DR PROSITE; PS51465; KAZAL_2; 1.
DR PROSITE; PS50106; PDZ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Disulfide bond; Hydrolase; Protease;
KW Reference proteome; Secreted; Serine protease; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..453
FT /note="Serine protease HTRA3"
FT /id="PRO_0000026949"
FT DOMAIN 21..77
FT /note="IGFBP N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653"
FT DOMAIN 64..128
FT /note="Kazal-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DOMAIN 359..444
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT REGION 175..340
FT /note="Serine protease"
FT ACT_SITE 191
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:26110759"
FT ACT_SITE 227
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:26110759"
FT ACT_SITE 305
FT /note="Charge relay system"
FT /evidence="ECO:0000269|PubMed:22229724,
FT ECO:0000269|PubMed:26110759"
FT DISULFID 76..101
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT DISULFID 90..126
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT VAR_SEQ 351..357
FT /note="DWKKRFI -> APSLAVH (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12513693"
FT /id="VSP_012570"
FT VAR_SEQ 358..453
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12513693"
FT /id="VSP_012571"
FT MUTAGEN 305
FT /note="S->A: Abolishes protease activity. Stabilizes the
FT protein."
FT /evidence="ECO:0000269|PubMed:22229724"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:4RI0"
FT HELIX 142..150
FT /evidence="ECO:0007829|PDB:4RI0"
FT HELIX 151..153
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 154..161
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 166..168
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 171..181
FT /evidence="ECO:0007829|PDB:4RI0"
FT TURN 182..184
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 185..188
FT /evidence="ECO:0007829|PDB:4RI0"
FT TURN 190..193
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 203..208
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 214..223
FT /evidence="ECO:0007829|PDB:4RI0"
FT TURN 224..227
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 228..233
FT /evidence="ECO:0007829|PDB:4RI0"
FT HELIX 247..249
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 255..260
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 268..274
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 294..298
FT /evidence="ECO:0007829|PDB:4RI0"
FT TURN 302..306
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 307..310
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 316..325
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 328..333
FT /evidence="ECO:0007829|PDB:4RI0"
FT HELIX 334..342
FT /evidence="ECO:0007829|PDB:4RI0"
FT STRAND 354..356
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 359..363
FT /evidence="ECO:0007829|PDB:2P3W"
FT HELIX 366..375
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 384..391
FT /evidence="ECO:0007829|PDB:2P3W"
FT HELIX 396..400
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 407..411
FT /evidence="ECO:0007829|PDB:2P3W"
FT HELIX 419..428
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 430..438
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 441..447
FT /evidence="ECO:0007829|PDB:2P3W"
FT STRAND 450..452
FT /evidence="ECO:0007829|PDB:2P3W"
SQ SEQUENCE 453 AA; 48608 MW; 3046FCDA1AB24FA6 CRC64;
MQARALLLAA LAALALAREP PAAPCPARCD VSRCPSPRCP GGYVPDLCNC CLVCAASEGE
PCGGPLDSPC GESLECVRGL CRCRWSHAVC GTDGHTYANV CALQAASRRA LQLSGTPVRQ
LQKGACPLGL HQLSSPRYKF NFIADVVEKI APAVVHIELF LRHPLFGRNV PLSSGSGFIM
SEAGLIITNA HVVSSNSAAP GRQQLKVQLQ NGDSYEATIK DIDKKSDIAT IKIHPKKKLP
VLLLGHSADL RPGEFVVAIG SPFALQNTVT TGIVSTAQRE GRELGLRDSD MDYIQTDAII
NYGNSGGPLV NLDGEVIGIN TLKVTAGISF AIPSDRITRF LTEFQDKQIK DWKKRFIGIR
MRTITPSLVD ELKASNPDFP EVSSGIYVQE VAPNSPSQRG GIQDGDIIVK VNGRPLVDSS
ELQEAVLTES PLLLEVRRGN DDLLFSIAPE VVM
