UniProtKB - O43464 (HTRA2_HUMAN)
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Protein
Serine protease HTRA2, mitochondrial
Gene
HTRA2
Organism
Homo sapiens (Human)
Status
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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Active sitei | 198 | Charge relay system1 Publication | 1 | |
Active sitei | 228 | Charge relay system1 Publication | 1 | |
Active sitei | 306 | Charge relay system1 Publication | 1 |
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
- adult walking behavior Source: Ensembl
- aging Source: Ensembl
- cellular protein catabolic process Source: ParkinsonsUK-UCL
- cellular response to growth factor stimulus Source: UniProtKB
- cellular response to heat Source: UniProtKB
- cellular response to interferon-beta Source: ParkinsonsUK-UCL
- cellular response to oxidative stress Source: ParkinsonsUK-UCL
- cellular response to retinoic acid Source: ParkinsonsUK-UCL
- ceramide metabolic process Source: Ensembl
- execution phase of apoptosis Source: UniProtKB
- forebrain development Source: Ensembl
- intrinsic apoptotic signaling pathway in response to DNA damage Source: ParkinsonsUK-UCL
- mitochondrion organization Source: Ensembl
- negative regulation of cell cycle Source: UniProtKB
- negative regulation of mitophagy in response to mitochondrial depolarization Source: Ensembl
- negative regulation of neuron death Source: ParkinsonsUK-UCL
- negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
- neuron development Source: Ensembl
- pentacyclic triterpenoid metabolic process Source: Ensembl
- positive regulation of apoptotic process Source: UniProtKB
- positive regulation of cell death Source: UniProtKB
- positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
- positive regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: ParkinsonsUK-UCL
- positive regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
- positive regulation of mitochondrion organization Source: ParkinsonsUK-UCL
- positive regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
- protein autoprocessing Source: ParkinsonsUK-UCL
- protein homotrimerization Source: CAFA
- proteolysis Source: ParkinsonsUK-UCL
- regulation of autophagy of mitochondrion Source: ParkinsonsUK-UCL
- regulation of multicellular organism growth Source: Ensembl
- response to herbicide Source: Ensembl
Keywordsi
Molecular function | Hydrolase, Protease, Serine protease |
Biological process | Apoptosis |
Enzyme and pathway databases
BRENDAi | 3.4.21.108. 2681. |
SIGNORi | O43464. |
Protein family/group databases
MEROPSi | S01.278. |
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 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000115317.11. |
HGNCi | HGNC:14348. HTRA2. |
MIMi | 606441. gene. |
neXtProti | NX_O43464. |
Subcellular locationi
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Transmembranei | 105 – 125 | HelicalSequence analysisAdd BLAST | 21 |
Keywords - Cellular componenti
Membrane, MitochondrionPathology & 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:617248Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_077960 | 243 – 244 | LP → PS in MGCA8; loss of protein expression. 1 PublicationCorresponds to variant dbSNP:rs1057519082Ensembl. | 2 | |
Natural variantiVAR_077961 | 404 | R → 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:rs767006508Ensembl. | 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:610297Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_046135 | 404 | R → W in PARK13. 1 Publication | 1 |
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 134 | A → M: Loss of interaction with XIAP. Loss of inhibition of XIAP activity. 1 Publication | 1 | |
Mutagenesisi | 306 | S → A: Loss of protease activity. 1 Publication | 1 |
Keywords - Diseasei
Disease mutation, Epilepsy, Neurodegeneration, Parkinson disease, ParkinsonismOrganism-specific databases
DisGeNETi | 27429. |
GeneReviewsi | HTRA2. |
MalaCardsi | HTRA2. |
MIMi | 168600. phenotype. 610297. phenotype. 617248. phenotype. |
OpenTargetsi | ENSG00000115317. |
Orphaneti | 2828. Young adult-onset Parkinsonism. |
PharmGKBi | PA33836. |
Polymorphism and mutation databases
BioMutai | HTRA2. |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Transit peptidei | 1 – 31 | MitochondrionAdd BLAST | 31 | |
PropeptideiPRO_0000026945 | 32 – 133 | 1 PublicationAdd BLAST | 102 | |
ChainiPRO_0000026946 | 134 – 458 | Serine protease HTRA2, mitochondrialAdd BLAST | 325 |
Post-translational modificationi
Autoproteolytically activated.
Keywords - PTMi
Autocatalytic cleavage, ZymogenProteomic databases
EPDi | O43464. |
MaxQBi | O43464. |
PaxDbi | O43464. |
PeptideAtlasi | O43464. |
PRIDEi | O43464. |
TopDownProteomicsi | O43464-2. [O43464-2] |
2D gel databases
OGPi | O43464. |
PTM databases
iPTMneti | O43464. |
PhosphoSitePlusi | O43464. |
Miscellaneous databases
PMAP-CutDBi | O43464. |
Expressioni
Tissue specificityi
Isoform 1 is ubiquitous. Isoform 2 is expressed predominantly in the kidney, colon and thyroid.
Gene expression databases
Bgeei | ENSG00000115317. |
CleanExi | HS_HTRA2. |
ExpressionAtlasi | O43464. baseline and differential. |
Genevisiblei | O43464. HS. |
Organism-specific databases
HPAi | CAB004004. 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
- identical protein binding Source: CAFA
- unfolded protein binding Source: UniProtKB
Protein-protein interaction databases
BioGridi | 118165. 70 interactors. |
CORUMi | O43464. |
ELMi | O43464. |
IntActi | O43464. 45 interactors. |
MINTi | O43464. |
STRINGi | 9606.ENSP00000258080. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more detailsFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Helixi | 143 – 147 | Combined sources | 5 | |
Helixi | 149 – 157 | Combined sources | 9 | |
Helixi | 158 – 160 | Combined sources | 3 | |
Beta strandi | 161 – 170 | Combined sources | 10 | |
Turni | 171 – 174 | Combined sources | 4 | |
Beta strandi | 175 – 188 | Combined sources | 14 | |
Turni | 189 – 191 | Combined sources | 3 | |
Beta strandi | 192 – 195 | Combined sources | 4 | |
Helixi | 198 – 200 | Combined sources | 3 | |
Beta strandi | 204 – 209 | Combined sources | 6 | |
Beta strandi | 211 – 213 | Combined sources | 3 | |
Beta strandi | 215 – 224 | Combined sources | 10 | |
Turni | 225 – 228 | Combined sources | 4 | |
Beta strandi | 229 – 233 | Combined sources | 5 | |
Helixi | 248 – 250 | Combined sources | 3 | |
Beta strandi | 256 – 259 | Combined sources | 4 | |
Beta strandi | 265 – 268 | Combined sources | 4 | |
Beta strandi | 271 – 275 | Combined sources | 5 | |
Beta strandi | 295 – 299 | Combined sources | 5 | |
Turni | 303 – 307 | Combined sources | 5 | |
Beta strandi | 308 – 311 | Combined sources | 4 | |
Beta strandi | 317 – 326 | Combined sources | 10 | |
Beta strandi | 329 – 334 | Combined sources | 6 | |
Helixi | 335 – 342 | Combined sources | 8 | |
Beta strandi | 359 – 361 | Combined sources | 3 | |
Beta strandi | 364 – 368 | Combined sources | 5 | |
Helixi | 371 – 380 | Combined sources | 10 | |
Beta strandi | 391 – 396 | Combined sources | 6 | |
Helixi | 401 – 405 | Combined sources | 5 | |
Beta strandi | 412 – 416 | Combined sources | 5 | |
Helixi | 424 – 433 | Combined sources | 10 | |
Beta strandi | 435 – 443 | Combined sources | 9 | |
Beta strandi | 446 – 452 | Combined sources | 7 | |
Beta strandi | 455 – 457 | Combined sources | 3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1LCY | X-ray | 2.00 | A | 134-458 | [»] | |
2PZD | X-ray | 2.75 | A/B | 359-458 | [»] | |
5FHT | X-ray | 1.95 | A | 134-458 | [»] | |
5M3N | X-ray | 1.65 | A | 134-458 | [»] | |
5M3O | X-ray | 1.70 | A | 134-458 | [»] | |
5TNY | X-ray | 1.70 | A | 134-458 | [»] | |
5TNZ | X-ray | 1.75 | A | 134-458 | [»] | |
5TO0 | X-ray | 1.90 | A | 134-458 | [»] | |
5TO1 | X-ray | 1.69 | A | 134-458 | [»] | |
DisProti | DP00315. | |||||
ProteinModelPortali | O43464. | |||||
SMRi | O43464. | |||||
ModBasei | Search... | |||||
MobiDBi | Search... |
Miscellaneous databases
EvolutionaryTracei | O43464. |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 364 – 445 | PDZPROSITE-ProRule annotationAdd BLAST | 82 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 166 – 342 | Serine proteaseAdd BLAST | 177 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 134 – 137 | IAP-binding motif | 4 |
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 helixPhylogenomic databases
eggNOGi | KOG1320. Eukaryota. COG0265. LUCA. |
GeneTreei | ENSGT00510000046315. |
HOGENOMi | HOG000223641. |
HOVERGENi | HBG052044. |
InParanoidi | O43464. |
KOi | K08669. |
OMAi | AHVVINK. |
OrthoDBi | EOG091G0LXR. |
PhylomeDBi | O43464. |
TreeFami | TF323480. |
Family and domain databases
InterProi | View protein in InterPro IPR001478. PDZ. IPR036034. PDZ_sf. IPR009003. Peptidase_S1_PA. IPR001940. Peptidase_S1C. |
Pfami | View protein in Pfam PF13180. PDZ_2. 1 hit. |
PRINTSi | PR00834. PROTEASES2C. |
SMARTi | View protein in SMART SM00228. PDZ. 1 hit. |
SUPFAMi | SSF50156. SSF50156. 1 hit. SSF50494. SSF50494. 1 hit. |
PROSITEi | View protein in PROSITE PS50106. PDZ. 1 hit. |
s (4)i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
This entry describes 4 produced by isoformsialternative splicing. AlignAdd to basket
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.
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
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_076967 | 12 | W → C1 PublicationCorresponds to variant dbSNP:rs775840965Ensembl. | 1 | |
Natural variantiVAR_046134 | 72 | L → P1 PublicationCorresponds to variant dbSNP:rs150047108Ensembl. | 1 | |
Natural variantiVAR_076968 | 128 | P → L1 PublicationCorresponds to variant dbSNP:rs757704467Ensembl. | 1 | |
Natural variantiVAR_027349 | 141 | A → S Polymorphism; may be a risk factor for Parkinson disease; reduced protease activity. 3 PublicationsCorresponds to variant dbSNP:rs72470544Ensembl. | 1 | |
Natural variantiVAR_076969 | 227 | A → S1 PublicationCorresponds to variant dbSNP:rs375322953Ensembl. | 1 | |
Natural variantiVAR_077960 | 243 – 244 | LP → PS in MGCA8; loss of protein expression. 1 PublicationCorresponds to variant dbSNP:rs1057519082Ensembl. | 2 | |
Natural variantiVAR_027350 | 399 | G → S Polymorphism; may be a risk factor for Parkinson disease; reduced protease activity. 4 PublicationsCorresponds to variant dbSNP:rs72470545Ensembl. | 1 | |
Natural variantiVAR_077961 | 404 | R → 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:rs767006508Ensembl. | 1 | |
Natural variantiVAR_046135 | 404 | R → W in PARK13. 1 Publication | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_005359 | 238 – 302 | Missing in isoform 2. 1 PublicationAdd BLAST | 65 | |
Alternative sequenceiVSP_005360 | 313 | L → LARELGAVSLQ in isoform 3. 1 Publication | 1 | |
Alternative sequenceiVSP_005362 | 314 – 458 | DGEVI…PEVTE → VSETSFLPRIPAPGQCGKGR FPLIQGCLVKFLSSSLLAIS QYPTRSPQHLLVLLFGCPHP LLFV in isoform 4. 1 PublicationAdd BLAST | 145 | |
Alternative sequenceiVSP_005361 | 372 – 403 | Missing in isoform 2 and isoform 3. 2 PublicationsAdd BLAST | 32 |
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. |
CCDSi | CCDS1951.1. [O43464-1] CCDS1952.1. [O43464-2] |
RefSeqi | NP_001308656.1. NM_001321727.1. [O43464-3] NP_037379.1. NM_013247.4. [O43464-1] NP_659540.1. NM_145074.2. [O43464-2] |
UniGenei | Hs.469045. Hs.744841. |
Genome annotation databases
Ensembli | ENST00000258080; ENSP00000258080; ENSG00000115317. [O43464-1] ENST00000352222; ENSP00000312893; ENSG00000115317. [O43464-2] |
GeneIDi | 27429. |
KEGGi | hsa:27429. |
UCSCi | uc002smi.2. human. [O43464-1] |
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Entry informationi
Entry namei | HTRA2_HUMAN | |
Accessioni | O43464Primary (citable) accession number: O43464 Secondary accession number(s): Q9HBZ4, Q9P0Y3, Q9P0Y4 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | September 26, 2001 |
Last sequence update: | May 1, 2000 | |
Last modified: | March 28, 2018 | |
This is version 194 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | 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. |