HtrA2

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.

HtrA2 Related Areas

Cancer>>Apoptosis>>Inhibitor of Apoptosis (IAP)>>HtrA2/PRSS25

Enzyme>>Protease & Regulator>>Serine Protease & Regulator>>Trypsin / PRSS>>HtrA2/PRSS25

HtrA2 Alternative Names

HtrA2, OMI, PARK13, PRSS25 [Homo sapiens]

HtrA2, AI481710, Omi, Prss25, mnd2 [Mus musculus]

Summaries for HtrA2

Entrez Gene summary for HtrA2:

This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional transcript variants have been described, but their full-length sequences have not been determined.

OMIM - description for HtrA2:

Wikipedia summary for HtrA2:

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene. This gene encodes a serine protease. HtrA2, also known as Omi, is a mitochondrially-located serine protease. HtrA2 can be released from the mitochondria during apoptosis and uses its four most N-terminal amino acids to mimic a caspase and be recruited by IAP caspase inhibitors such as XIAP and CIAP1/2. Once bound, the serine protease cleaves the IAP, reducing the cell's inhibition to caspase activation. Additionally, HtrA2 has a PDZ domain, though little is known about its ability to bind PDZ binding motif peptides. HtrA2 has recently been identified as a gene related to Parkinson's disease. Mutations in Htra2 have been found in patients suffering from Parkinson's disease. Additionally, mice lacking HtrA2 have a parkinsonian phenotype. This suggests that HtrA2 is linked to Parkinson's disease progression in humans and mice. HtrA2 shows similarities with DegS, a bacterial protease present in the periplasm of gram-negative bacteria. Structurally, HtrA2 is a trimeric molecule with central protease domains and carboxy-terminal PDZ domains.

Human HtrA2 Protein General Information

 

• Protein names: Recommended name: Serine protease HTRA2, mitochondrial
• Sequence length: 458 AA.
• Domain: The mature N-terminus is involved in the interaction with XIAP. The PDZ domain mediates interaction with MXI2.
• Sequence similarities: 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.
• Post-translational modification: Autoproteolytically activated.
• Subunit structure: Belongs to the peptidase S1B family. Contains 1 PDZ (DHR) domain. Ontologies
• Subcellular location: Mitochondrion intermembrane space. Mitochondrion membrane; Single-pass membrane protein Potential. Note: Predominantly present in the intermembrane space. Released into the cytosol following apoptotic stimuli, such as UV treatment, and stimulation of mitochondria with caspase-8 truncated BID/tBID.
• Tissue specificity: Isoform 1 is ubiquitous. Isoform 2 is expressed predominantly in the kidney, colon and thyroid.
• Involvement in disease: Defects in HTRA2 are the cause of Parkinson disease type 13 (PARK13) [MIM:610297]. A 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.

General information above from UniProt

Function for HtrA2 Protein

UniProtKB:

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.

Genatlas:

• HtrA2 promote cytochrome c (Cyt c)dependent caspase activation
• HtrA2 induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4 (BIRC)
• serine-type endopeptidase involved in stress response pathways
• HtrA2 is released from mitochondria and inhibits the function of XIAP
• HtrA2 is a SMAC-like inhibitor of IAP (inhibitor of apoptosis proteins) activity
• could have protective functions in mitochondria
• a proapoptotic molecule that proteolyses several proteins to induce cell death
• its protease activity is involved not only in apoptosis but also in cellular homeostasis
• inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular inducers of mitochondrial stress

Homology for human HtrA2

• homolog to murine Htra2
• homolog to HTRA1

Phenotype Information for HtrA2

• Gene/Locus: HTRA2, OMI, PARK13, PRSS25
• Phenotype: Parkinson disease 13

Phenotype Information for HtrA2 from OMIM (Online Mendelian Inheritance in Man)