P83110 (HTRA3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine protease HTRA3
EC=3.4.21.-

Alternative name(s):
High-temperature requirement factor A3
Pregnancy-related serine protease

Gene names

Name:	HTRA3
Synonyms:	PRSP

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	453 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 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. Ref.7
Subunit structure	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. Ref.8
Subcellular location	Secreted. Note: Secretion increased during decidualization of endometrial stromal cells. Ref.7
Tissue specificity	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. Ref.1 Ref.5 Ref.7
Induction	Down-regulated in ovarian and endometrial cancers (EC). Decrease of 3.2-fold in endometrial cancer. Ref.5 Ref.6
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	Secreted
Coding sequence diversity	Alternative splicing
Domain	Signal
Molecular function	Hydrolase Protease Serine protease
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of BMP signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transforming growth factor beta receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB proteolysis Inferred from direct assay Ref.8. Source: UniProtKB regulation of cell growth Inferred from electronic annotation. Source: InterPro
Cellular_component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	endopeptidase activity Inferred from direct assay PubMed 18387192. Source: BHF-UCL serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro serine-type peptidase activity Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P83110-1)

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.

Isoform 2 (identifier: P83110-2)

Also known as: Short; pS;

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 17

17

Potential

Chain

18 – 453

436

Serine protease HTRA3

PRO_0000026949

Regions

Domain

21 – 77

57

IGFBP N-terminal

Domain

64 – 128

65

Kazal-like

Domain

359 – 444

86

PDZ

Region

175 – 340

166

Serine protease

Sites

Active site

191

1

Charge relay system Potential

Active site

227

1

Charge relay system Potential

Active site

305

1

Charge relay system

Natural variations

Alternative sequence

351 – 357

7

DWKKRFI → APSLAVH in isoform 2.

VSP_012570

Alternative sequence

358 – 453

96

Missing in isoform 2.

VSP_012571

Experimental info

Mutagenesis

305

1

S → A: Abolishes protease activity. Stabilizes the protein. Ref.8

Secondary structure

1

.

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453

Helix Strand Turn

Details...

Beta strand

354 – 356

3

Beta strand

359 – 363

5

Helix

366 – 375

10

Beta strand

384 – 391

8

Helix

396 – 400

5

Beta strand

407 – 411

5

Helix

419 – 428

10

Beta strand

430 – 438

9

Beta strand

441 – 447

7

Beta strand

450 – 452

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Long) (pL) [UniParc]. Last modified June 20, 2002. Version 2. Checksum: 3046FCDA1AB24FA6	FASTA	453	48,608
	10 20 30 40 50 60 MQARALLLAA LAALALAREP PAAPCPARCD VSRCPSPRCP GGYVPDLCNC CLVCAASEGE 70 80 90 100 110 120 PCGGPLDSPC GESLECVRGL CRCRWSHAVC GTDGHTYANV CALQAASRRA LQLSGTPVRQ 130 140 150 160 170 180 LQKGACPLGL HQLSSPRYKF NFIADVVEKI APAVVHIELF LRHPLFGRNV PLSSGSGFIM 190 200 210 220 230 240 SEAGLIITNA HVVSSNSAAP GRQQLKVQLQ NGDSYEATIK DIDKKSDIAT IKIHPKKKLP 250 260 270 280 290 300 VLLLGHSADL RPGEFVVAIG SPFALQNTVT TGIVSTAQRE GRELGLRDSD MDYIQTDAII 310 320 330 340 350 360 NYGNSGGPLV NLDGEVIGIN TLKVTAGISF AIPSDRITRF LTEFQDKQIK DWKKRFIGIR 370 380 390 400 410 420 MRTITPSLVD ELKASNPDFP EVSSGIYVQE VAPNSPSQRG GIQDGDIIVK VNGRPLVDSS 430 440 450 ELQEAVLTES PLLLEVRRGN DDLLFSIAPE VVM
	Isoform 2 (Short) (pS) [UniParc]. Checksum: 8A62D2B9823BC420	FASTA	357	37,940
	10 20 30 40 50 60 MQARALLLAA LAALALAREP PAAPCPARCD VSRCPSPRCP GGYVPDLCNC CLVCAASEGE 70 80 90 100 110 120 PCGGPLDSPC GESLECVRGL CRCRWSHAVC GTDGHTYANV CALQAASRRA LQLSGTPVRQ 130 140 150 160 170 180 LQKGACPLGL HQLSSPRYKF NFIADVVEKI APAVVHIELF LRHPLFGRNV PLSSGSGFIM 190 200 210 220 230 240 SEAGLIITNA HVVSSNSAAP GRQQLKVQLQ NGDSYEATIK DIDKKSDIAT IKIHPKKKLP 250 260 270 280 290 300 VLLLGHSADL RPGEFVVAIG SPFALQNTVT TGIVSTAQRE GRELGLRDSD MDYIQTDAII 310 320 330 340 350 NYGNSGGPLV NLDGEVIGIN TLKVTAGISF AIPSDRITRF LTEFQDKQIK APSLAVH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00027862.
IPI00514571.

RefSeq

NP_444272.1. NM_053044.3.

UniGene

Hs.479119.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2P3W	X-ray	1.70	A/B	354-453	[»]

ProteinModelPortal

P83110.

ModBase

Search...

Protein-protein interaction databases

IntAct

P83110. 2 interactions.

STRING

9606.ENSP00000303766.

Protein family/group databases

MEROPS

S01.284.

PTM databases

PhosphoSite

P83110.

Polymorphism databases

DMDM

21542412.

Proteomic databases

PaxDb

P83110.

PRIDE

P83110.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000307358; ENSP00000303766; ENSG00000170801.
ENST00000382512; ENSP00000371952; ENSG00000170801.

GeneID

94031.

KEGG

hsa:94031.

UCSC

uc003gkz.3. human.
uc003gla.3. human.

Organism-specific databases

CTD

94031.

GeneCards

GC04P008271.

HGNC

HGNC:30406. HTRA3.

HPA

HPA021187.

MIM

608785. gene.

neXtProt

NX_P83110.

PharmGKB

PA134908281.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0265.

HOGENOM

HOG000223641.

HOVERGEN

HBG052044.

InParanoid

P83110.

KO

K08785.

OMA

ACPSGLH.

OrthoDB

EOG4KH2V3.

PhylomeDB

P83110.

Gene expression databases

Bgee

P83110.

CleanEx

HS_HTRA3.

Genevestigator

P83110.

GermOnline

ENSG00000170801. 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

PF07648. Kazal_2. 1 hit.
PF13180. PDZ_2. 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

PS00222. IGFBP_N_1. False negative.
PS51323. IGFBP_N_2. 1 hit.
PS00282. KAZAL_1. False negative.
PS51465. KAZAL_2. 1 hit.
PS50106. PDZ. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P83110.

GenomeRNAi

94031.

NextBio

78335.

SOURCE

Search...

Entry information

Entry name

HTRA3_HUMAN

Accession

Primary (citable) accession number: P83110
Secondary accession number(s): Q7Z7A2

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 26, 2001
Last sequence update:	June 20, 2002
Last modified:	May 1, 2013
This is version 108 of the entry and version 2 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.