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 of 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]
^Bowden MA, Di Nezza-Cossens LA, Jobling T, Salamonsen LA, Nie G (Oct 2006). "Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer". Gynecologic Oncology. 103 (1): 253–60.
doi:
10.1016/j.ygyno.2006.03.006.
PMID16650464.
^Narkiewicz J, Klasa-Mazurkiewicz D, Zurawa-Janicka D, Skorko-Glonek J, Emerich J, Lipinska B (May 2008). "Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer". Clinical Biochemistry. 41 (7–8): 561–9.
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PMID17718385.
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PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56.
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PMID9373149.
Savopoulos JW, Carter PS, Turconi S, Pettman GR, Karran EH, Gray CW, Ward RV, Jenkins O, Creasy CL (Jul 2000). "Expression, purification, and functional analysis of the human serine protease HtrA2". Protein Expression and Purification. 19 (2): 227–34.
doi:
10.1006/prep.2000.1240.
PMID10873535.
Faccio L, Fusco C, Viel A, Zervos AS (Sep 2000). "Tissue-specific splicing of Omi stress-regulated endoprotease leads to an inactive protease with a modified PDZ motif". Genomics. 68 (3): 343–7.
doi:
10.1006/geno.2000.6263.
PMID10995577.
Li W, Srinivasula SM, Chai J, Li P, Wu JW, Zhang Z, Alnemri ES, Shi Y (Jun 2002). "Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi". Nature Structural Biology. 9 (6): 436–41.
doi:
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PMID11967569.
S2CID21170905.