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Protein

Serine protease HTRA2, mitochondrial

Gene

HTRA2

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

Functioni

Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive.2 Publications

Catalytic activityi

Cleavage of non-polar aliphatic amino-acids at the P1 position, with a preference for Val, Ile and Met. At the P2 and P3 positions, Arg is selected most strongly with a secondary preference for other hydrophilic residues.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei198Charge relay system1 Publication1
Active sitei228Charge relay system1 Publication1
Active sitei306Charge relay system1 Publication1

GO - Molecular functioni

  • identical protein binding Source: CAFA
  • peptidase activity Source: UniProtKB
  • serine-type endopeptidase activity Source: UniProtKB
  • serine-type peptidase activity Source: UniProtKB
  • unfolded protein binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Serine protease
Biological processApoptosis

Enzyme and pathway databases

BRENDAi3.4.21.108 2681
SIGNORiO43464

Protein family/group databases

MEROPSiS01.278
MoonDBiO43464 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Serine protease HTRA2, mitochondrial (EC:3.4.21.108)
Alternative name(s):
High temperature requirement protein A2
Short name:
HtrA2
Omi stress-regulated endoprotease
Serine protease 25
Serine proteinase OMI
Gene namesi
Name:HTRA2
Synonyms:OMI, PRSS25
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000115317.11
HGNCiHGNC:14348 HTRA2
MIMi606441 gene
neXtProtiNX_O43464

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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei105 – 125HelicalSequence analysisAdd BLAST21

Keywords - Cellular componenti

Membrane, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

3-methylglutaconic aciduria 8 (MGCA8)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive inborn error of metabolism resulting in early death. Clinical features include extreme hypertonia observed at birth, alternating with hypotonia, subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, and intractable seizures. Patients show lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, and progressive brain atrophy.
See also OMIM:617248
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_077960243 – 244LP → PS in MGCA8; loss of protein expression. 1 PublicationCorresponds to variant dbSNP:rs1057519082Ensembl.2
Natural variantiVAR_077961404R → Q in MGCA8; may lead to skipping of exon 7 and the resultant protein may be truncated; loss of protein expression in patient cells homozygous for the mutation. 1 PublicationCorresponds to variant dbSNP:rs767006508EnsemblClinVar.1
Parkinson disease 13 (PARK13)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain.
See also OMIM:610297
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_046135404R → W in PARK13. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi134A → M: Loss of interaction with XIAP. Loss of inhibition of XIAP activity. 1 Publication1
Mutagenesisi306S → A: Loss of protease activity. 1 Publication1

Keywords - Diseasei

Disease mutation, Epilepsy, Neurodegeneration, Parkinson disease, Parkinsonism

Organism-specific databases

DisGeNETi27429
GeneReviewsiHTRA2
MalaCardsiHTRA2
MIMi168600 phenotype
610297 phenotype
617248 phenotype
OpenTargetsiENSG00000115317
Orphaneti2828 Young adult-onset Parkinsonism
PharmGKBiPA33836

Polymorphism and mutation databases

BioMutaiHTRA2

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 31MitochondrionAdd BLAST31
PropeptideiPRO_000002694532 – 1331 PublicationAdd BLAST102
ChainiPRO_0000026946134 – 458Serine protease HTRA2, mitochondrialAdd BLAST325

Post-translational modificationi

Autoproteolytically activated.

Keywords - PTMi

Autocatalytic cleavage, Zymogen

Proteomic databases

EPDiO43464
MaxQBiO43464
PaxDbiO43464
PeptideAtlasiO43464
PRIDEiO43464
ProteomicsDBi48958
48959 [O43464-2]
48960 [O43464-3]
48961 [O43464-4]
TopDownProteomicsiO43464-2 [O43464-2]

2D gel databases

OGPiO43464

PTM databases

iPTMnetiO43464
PhosphoSitePlusiO43464

Miscellaneous databases

PMAP-CutDBiO43464

Expressioni

Tissue specificityi

Isoform 1 is ubiquitous. Isoform 2 is expressed predominantly in the kidney, colon and thyroid.

Gene expression databases

BgeeiENSG00000115317 Expressed in 221 organ(s), highest expression level in liver
CleanExiHS_HTRA2
ExpressionAtlasiO43464 baseline and differential
GenevisibleiO43464 HS

Organism-specific databases

HPAiCAB004004
HPA006602
HPA027366

Interactioni

Subunit structurei

Homotrimer. Interacts with MXI2. Interacts with THAP5 under apoptotic conditions. The mature protein, but not the precursor, binds to BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with BIRC6/bruce.4 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi118165, 71 interactors
CORUMiO43464
ELMiO43464
IntActiO43464, 47 interactors
MINTiO43464
STRINGi9606.ENSP00000258080

Structurei

Secondary structure

1458
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

DisProtiDP00315
ProteinModelPortaliO43464
SMRiO43464
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO43464

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini364 – 445PDZPROSITE-ProRule annotationAdd BLAST82

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni166 – 342Serine proteaseAdd BLAST177

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi134 – 137IAP-binding motif4

Domaini

The mature N-terminus is involved in the interaction with XIAP.
The PDZ domain mediates interaction with MXI2.

Sequence similaritiesi

Belongs to the peptidase S1C family.Curated

Keywords - Domaini

Transit peptide, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1320 Eukaryota
COG0265 LUCA
GeneTreeiENSGT00510000046315
HOGENOMiHOG000223641
HOVERGENiHBG052044
InParanoidiO43464
KOiK08669
OMAiAHVVINK
OrthoDBiEOG091G0LXR
PhylomeDBiO43464
TreeFamiTF323480

Family and domain databases

InterProiView protein in InterPro
IPR001478 PDZ
IPR036034 PDZ_sf
IPR009003 Peptidase_S1_PA
IPR001940 Peptidase_S1C
PfamiView protein in Pfam
PF13180 PDZ_2, 1 hit
PRINTSiPR00834 PROTEASES2C
SMARTiView protein in SMART
SM00228 PDZ, 1 hit
SUPFAMiSSF50156 SSF50156, 1 hit
SSF50494 SSF50494, 1 hit
PROSITEiView protein in PROSITE
PS50106 PDZ, 1 hit

Sequences (4+)i

Sequence statusi: Complete.

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

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 4 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: O43464-1) [UniParc]FASTAAdd to basket
Also known as: 13B

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
MAAPRAGRGA GWSLRAWRAL GGIRWGRRPR LTPDLRALLT SGTSDPRARV
60 70 80 90 100
TYGTPSLWAR LSVGVTEPRA CLTSGTPGPR AQLTAVTPDT RTREASENSG
110 120 130 140 150
TRSRAWLAVA LGAGGAVLLL LWGGGRGPPA VLAAVPSPPP ASPRSQYNFI
160 170 180 190 200
ADVVEKTAPA VVYIEILDRH PFLGREVPIS NGSGFVVAAD GLIVTNAHVV
210 220 230 240 250
ADRRRVRVRL LSGDTYEAVV TAVDPVADIA TLRIQTKEPL PTLPLGRSAD
260 270 280 290 300
VRQGEFVVAM GSPFALQNTI TSGIVSSAQR PARDLGLPQT NVEYIQTDAA
310 320 330 340 350
IDFGNSGGPL VNLDGEVIGV NTMKVTAGIS FAIPSDRLRE FLHRGEKKNS
360 370 380 390 400
SSGISGSQRR YIGVMMLTLS PSILAELQLR EPSFPDVQHG VLIHKVILGS
410 420 430 440 450
PAHRAGLRPG DVILAIGEQM VQNAEDVYEA VRTQSQLAVQ IRRGRETLTL

YVTPEVTE
Length:458
Mass (Da):48,841
Last modified:May 1, 2000 - v2
Checksum:iCEA955A7D0DD8C0D
GO
Isoform 2 (identifier: O43464-2) [UniParc]FASTAAdd to basket
Also known as: D-Omi

The sequence of this isoform differs from the canonical sequence as follows:
     238-302: Missing.
     372-403: Missing.

Show »
Length:361
Mass (Da):38,493
Checksum:iBD0824D4308140D7
GO
Isoform 3 (identifier: O43464-3) [UniParc]FASTAAdd to basket
Also known as: p7

The sequence of this isoform differs from the canonical sequence as follows:
     313-313: L → LARELGAVSLQ
     372-403: Missing.

Show »
Length:436
Mass (Da):46,382
Checksum:iB48266A8EB7E4EE8
GO
Isoform 4 (identifier: O43464-4) [UniParc]FASTAAdd to basket
Also known as: p4

The sequence of this isoform differs from the canonical sequence as follows:
     314-458: DGEVIGVNTM...TLYVTPEVTE → VSETSFLPRI...FGCPHPLLFV

Show »
Length:377
Mass (Da):39,914
Checksum:i14D0982E08A58FB2
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0C4DG44A0A0C4DG44_HUMAN
Serine protease HTRA2, mitochondria...
HTRA2
423Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07696712W → C1 PublicationCorresponds to variant dbSNP:rs775840965Ensembl.1
Natural variantiVAR_04613472L → P1 PublicationCorresponds to variant dbSNP:rs150047108EnsemblClinVar.1
Natural variantiVAR_076968128P → L1 PublicationCorresponds to variant dbSNP:rs757704467Ensembl.1
Natural variantiVAR_027349141A → S Polymorphism; may be a risk factor for Parkinson disease; reduced protease activity. 3 PublicationsCorresponds to variant dbSNP:rs72470544EnsemblClinVar.1
Natural variantiVAR_076969227A → S1 PublicationCorresponds to variant dbSNP:rs375322953Ensembl.1
Natural variantiVAR_077960243 – 244LP → PS in MGCA8; loss of protein expression. 1 PublicationCorresponds to variant dbSNP:rs1057519082Ensembl.2
Natural variantiVAR_027350399G → S Polymorphism; may be a risk factor for Parkinson disease; reduced protease activity. 4 PublicationsCorresponds to variant dbSNP:rs72470545EnsemblClinVar.1
Natural variantiVAR_077961404R → Q in MGCA8; may lead to skipping of exon 7 and the resultant protein may be truncated; loss of protein expression in patient cells homozygous for the mutation. 1 PublicationCorresponds to variant dbSNP:rs767006508EnsemblClinVar.1
Natural variantiVAR_046135404R → W in PARK13. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_005359238 – 302Missing in isoform 2. 1 PublicationAdd BLAST65
Alternative sequenceiVSP_005360313L → LARELGAVSLQ in isoform 3. 1 Publication1
Alternative sequenceiVSP_005362314 – 458DGEVI…PEVTE → VSETSFLPRIPAPGQCGKGR FPLIQGCLVKFLSSSLLAIS QYPTRSPQHLLVLLFGCPHP LLFV in isoform 4. 1 PublicationAdd BLAST145
Alternative sequenceiVSP_005361372 – 403Missing in isoform 2 and isoform 3. 2 PublicationsAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF020760 mRNA Translation: AAB94569.2
AF141305 mRNA Translation: AAF66596.1
AF141306 mRNA Translation: AAF66597.1
AF141307 mRNA Translation: AAF66598.1
AF184911 mRNA Translation: AAG13126.1
AC006544 Genomic DNA No translation available.
BC000096 mRNA Translation: AAH00096.1
CCDSiCCDS1951.1 [O43464-1]
CCDS1952.1 [O43464-2]
RefSeqiNP_001308656.1, NM_001321727.1 [O43464-3]
NP_037379.1, NM_013247.4 [O43464-1]
NP_659540.1, NM_145074.2 [O43464-2]
UniGeneiHs.469045
Hs.744841

Genome annotation databases

EnsembliENST00000258080; ENSP00000258080; ENSG00000115317 [O43464-1]
ENST00000352222; ENSP00000312893; ENSG00000115317 [O43464-2]
GeneIDi27429
KEGGihsa:27429
UCSCiuc002smi.2 human [O43464-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF020760 mRNA Translation: AAB94569.2
AF141305 mRNA Translation: AAF66596.1
AF141306 mRNA Translation: AAF66597.1
AF141307 mRNA Translation: AAF66598.1
AF184911 mRNA Translation: AAG13126.1
AC006544 Genomic DNA No translation available.
BC000096 mRNA Translation: AAH00096.1
CCDSiCCDS1951.1 [O43464-1]
CCDS1952.1 [O43464-2]
RefSeqiNP_001308656.1, NM_001321727.1 [O43464-3]
NP_037379.1, NM_013247.4 [O43464-1]
NP_659540.1, NM_145074.2 [O43464-2]
UniGeneiHs.469045
Hs.744841

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LCYX-ray2.00A134-458[»]
2PZDX-ray2.75A/B359-458[»]
5FHTX-ray1.95A134-458[»]
5M3NX-ray1.65A134-458[»]
5M3OX-ray1.70A134-458[»]
5TNYX-ray1.70A134-458[»]
5TNZX-ray1.75A134-458[»]
5TO0X-ray1.90A134-458[»]
5TO1X-ray1.69A134-458[»]
5WYNX-ray2.05A134-458[»]
DisProtiDP00315
ProteinModelPortaliO43464
SMRiO43464
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118165, 71 interactors
CORUMiO43464
ELMiO43464
IntActiO43464, 47 interactors
MINTiO43464
STRINGi9606.ENSP00000258080

Protein family/group databases

MEROPSiS01.278
MoonDBiO43464 Predicted

PTM databases

iPTMnetiO43464
PhosphoSitePlusiO43464

Polymorphism and mutation databases

BioMutaiHTRA2

2D gel databases

OGPiO43464

Proteomic databases

EPDiO43464
MaxQBiO43464
PaxDbiO43464
PeptideAtlasiO43464
PRIDEiO43464
ProteomicsDBi48958
48959 [O43464-2]
48960 [O43464-3]
48961 [O43464-4]
TopDownProteomicsiO43464-2 [O43464-2]

Protocols and materials databases

DNASUi27429
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000258080; ENSP00000258080; ENSG00000115317 [O43464-1]
ENST00000352222; ENSP00000312893; ENSG00000115317 [O43464-2]
GeneIDi27429
KEGGihsa:27429
UCSCiuc002smi.2 human [O43464-1]

Organism-specific databases

CTDi27429
DisGeNETi27429
EuPathDBiHostDB:ENSG00000115317.11
GeneCardsiHTRA2
GeneReviewsiHTRA2
HGNCiHGNC:14348 HTRA2
HPAiCAB004004
HPA006602
HPA027366
MalaCardsiHTRA2
MIMi168600 phenotype
606441 gene
610297 phenotype
617248 phenotype
neXtProtiNX_O43464
OpenTargetsiENSG00000115317
Orphaneti2828 Young adult-onset Parkinsonism
PharmGKBiPA33836
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1320 Eukaryota
COG0265 LUCA
GeneTreeiENSGT00510000046315
HOGENOMiHOG000223641
HOVERGENiHBG052044
InParanoidiO43464
KOiK08669
OMAiAHVVINK
OrthoDBiEOG091G0LXR
PhylomeDBiO43464
TreeFamiTF323480

Enzyme and pathway databases

BRENDAi3.4.21.108 2681
SIGNORiO43464

Miscellaneous databases

ChiTaRSiHTRA2 human
EvolutionaryTraceiO43464
GeneWikiiHtrA_serine_peptidase_2
GenomeRNAii27429
PMAP-CutDBiO43464
PROiPR:O43464
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000115317 Expressed in 221 organ(s), highest expression level in liver
CleanExiHS_HTRA2
ExpressionAtlasiO43464 baseline and differential
GenevisibleiO43464 HS

Family and domain databases

InterProiView protein in InterPro
IPR001478 PDZ
IPR036034 PDZ_sf
IPR009003 Peptidase_S1_PA
IPR001940 Peptidase_S1C
PfamiView protein in Pfam
PF13180 PDZ_2, 1 hit
PRINTSiPR00834 PROTEASES2C
SMARTiView protein in SMART
SM00228 PDZ, 1 hit
SUPFAMiSSF50156 SSF50156, 1 hit
SSF50494 SSF50494, 1 hit
PROSITEiView protein in PROSITE
PS50106 PDZ, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiHTRA2_HUMAN
AccessioniPrimary (citable) accession number: O43464
Secondary accession number(s): Q9HBZ4, Q9P0Y3, Q9P0Y4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: May 1, 2000
Last modified: October 10, 2018
This is version 200 of the entry and version 2 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 2
    Human chromosome 2: 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. Peptidase families
    Classification of peptidase families and list of entries
  4. SIMILARITY comments
    Index of protein domains and families
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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