Serine protease HTRA2, mitochondrial
Enzyme found in humans
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Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene.[5][6][7] This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.[8][9]
Structure
Gene
The gene HTRA2 encodes a serine protease. The human gene has 8 exons and locates at chromosome band 2p12.
Protein
Protein HtrA2, also known as Omi, is a mitochondrially-located serine protease. The human protein Serine protease HTRA2, mitochondrial is 49kDa in size and composed of 458 amino acids. The peptide fragment of 1-31 amino acid is the mitochondrial transition sequence, fragment 32-133 amino acid is propertied, and 134-458 is the mature protein Serine protease HTRA2, mitochondrial, and its theoretical pI of this protein is 6.12.[10] 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 a carboxy-terminal PDZ domain, which is characteristic of the HtrA family. The PDZ domain preferentially binds C-terminus of the protein substrate and modulate the proteolytic activity of the trypsin-like protease domain.[11]
Function
The high-temperature requirement (HtrA) family are conserved evolutionarily and these oligomeric serine proteases has been classified in family S1B of the PA protease clan in the MEROPS protease database.[11] The protease activity of the HtrA member HtrA2/Omi is required for mitochondrial homeostasis in mice and humans and inactivating mutations associated with neurodegenerative disorders such as Parkinson's disease.[8] Moreover, HtrA2/Omi is released in the cytosol from the mitochondria during apoptosis and uses its four most N-terminal amino acids to mimic a caspase and be recruited by inhibitor of apoptosis protein (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. In summary, HTRA2/Omi contributes to apoptosis through both caspase-dependent and -independent pathways.
Clinical significance
The members of the HtrA family of proteases have been shown playing critical roles in cell physiology and being involved in several pathological processes including cancer[12] and neurodegenerative disease.[11] Strong evidences supported HtrA2's involvement in oncogenesis. This protein is widely expressed in a variety of cancer cell lines,[13][14][15][16] Analysis of biopsy samples showed changes in expression of HtrA2 in cancer tissues compared with normal tissues.
HtrA2 has recently been identified as a gene related to Parkinson's disease. Mutations in Htra2 have been found in patients with 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.[9]