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. 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.
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. 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. 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.
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 and neurodegenerative disease. Strong evidences supported of HtrA2's involvement in oncogenesis. This protein is widely expressed in a variety of cancer cell lines, 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 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.
^ abFaccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS (Jan 2000). "Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia". The Journal of Biological Chemistry. 275 (4): 2581–8. doi:10.1074/jbc.275.4.2581. PMID10644717.
^Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, Southan C, Barton A, Fantom KG, West A, Savopoulos J, Hassan NJ, Clinkenbeard H, Hanning C, Amegadzie B, Davis JB, Dingwall C, Livi GP, Creasy CL (Sep 2000). "Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response". European Journal of Biochemistry / FEBS. 267 (18): 5699–710. doi:10.1046/j.1432-1327.2000.01589.x. PMID10971580.
^ abcVande Walle L, Lamkanfi M, Vandenabeele P (Mar 2008). "The mitochondrial serine protease HtrA2/Omi: an overview". Cell Death and Differentiation. 15 (3): 453–60. doi:10.1038/sj.cdd.4402291. PMID18174901.
^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. doi:10.1016/j.clinbiochem.2008.01.004. PMID18241672.
^Zurawa-Janicka D, Kobiela J, Stefaniak T, Wozniak A, Narkiewicz J, Wozniak M, Limon J, Lipinska B (2008). "Changes in expression of serine proteases HtrA1 and HtrA2 during estrogen-induced oxidative stress and nephrocarcinogenesis in male Syrian hamster". Acta Biochimica Polonica. 55 (1): 9–19. PMID18231652.
^ abHegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES (Oct 2003). "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein". The Journal of Biological Chemistry. 278 (40): 38699–706. doi:10.1074/jbc.M303179200. PMID12865429.
^ abVerhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (Jan 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". The Journal of Biological Chemistry. 277 (1): 445–54. doi:10.1074/jbc.M109891200. PMID11604410.
Zurawa-Janicka D, Narkiewicz J, Lipińska B (2007). "[Characterization of the HtrA family of proteins]". Postepy Biochemii. 53 (1): 27–36. PMID17718385.
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. 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. doi:10.1016/S0378-1119(97)00411-3. 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.
Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (Sep 2001). "A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death". Molecular Cell. 8 (3): 613–21. doi:10.1016/S1097-2765(01)00341-0. PMID11583623.
Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL (Jan 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". The Journal of Biological Chemistry. 277 (1): 445–54. doi:10.1074/jbc.M109891200. PMID11604410.
Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (Jan 2002). "Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction". The Journal of Biological Chemistry. 277 (1): 432–8. doi:10.1074/jbc.M109721200. PMID11606597.
Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ, Dixit VM (Apr 2002). "SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)". The Journal of Biological Chemistry. 277 (14): 12275–9. doi:10.1074/jbc.M112045200. PMID11801603.
van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P (Jan 2002). "The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity". Cell Death and Differentiation. 9 (1): 20–6. doi:10.1038/sj.cdd.4400970. PMID11803371.
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:10.1038/nsb795. PMID11967569.
Srinivasula SM, Gupta S, Datta P, Zhang Z, Hegde R, Cheong N, Fernandes-Alnemri T, Alnemri ES (Aug 2003). "Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2". The Journal of Biological Chemistry. 278 (34): 31469–72. doi:10.1074/jbc.C300240200. PMID12835328.
Suzuki Y, Takahashi-Niki K, Akagi T, Hashikawa T, Takahashi R (Feb 2004). "Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways". Cell Death and Differentiation. 11 (2): 208–16. doi:10.1038/sj.cdd.4401343. PMID14605674.
Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T (Mar 2004). "A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity". Blood. 103 (6): 2299–307. doi:10.1182/blood-2003-05-1605. PMID14645012.
Park HJ, Seong YM, Choi JY, Kang S, Rhim H (Feb 2004). "Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi". Neuroscience Letters. 357 (1): 63–7. doi:10.1016/j.neulet.2003.11.068. PMID15036614.
Guo Y, Cheong N, Zhang Z, De Rose R, Deng Y, Farber SA, Fernandes-Alnemri T, Alnemri ES (Jun 2004). "Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death". The Journal of Biological Chemistry. 279 (23): 24813–25. doi:10.1074/jbc.M402049200. PMID15044455.