HtrA serine peptidase 2
Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene.[1][2][3] 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.
Interactions
HtrA serine peptidase 2 has been shown to interact with MAPK14,[1] XIAP[4][5] and BIRC2.[4][5]
References
- ^ a b Faccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS (Feb 2000). "Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia". J Biol Chem 275 (4): 2581–8. doi:10.1074/jbc.275.4.2581. PMID 10644717.
- ^ 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 (Oct 2000). "Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response". Eur J Biochem 267 (18): 5699–710. doi:10.1046/j.1432-1327.2000.01589.x. PMID 10971580.
- ^ "Entrez Gene: HTRA2 HtrA serine peptidase 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27429.
- ^ a b Hegde, Ramesh; Srinivasula Srinivasa M, Datta Pinaki, Madesh Muniswamy, Wassell Richard, Zhang ZhiJia, Cheong NaEun, Nejmeh Julie, Fernandes-Alnemri Teresa, Hoshino Shin-ichi, Alnemri Emad S (Oct. 2003). "The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein". J. Biol. Chem. (United States) 278 (40): 38699–706. doi:10.1074/jbc.M303179200. ISSN 0021-9258. PMID 12865429.
- ^ a b Verhagen, Anne M; Silke John, Ekert Paul G, Pakusch Miha, Kaufmann Hitto, Connolly Lisa M, Day Catherine L, Tikoo Anjali, Burke Richard, Wrobel Carolyn, Moritz Robert L, Simpson Richard J, Vaux David L (Jan. 2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". J. Biol. Chem. (United States) 277 (1): 445–54. doi:10.1074/jbc.M109891200. ISSN 0021-9258. PMID 11604410.
Further reading
- Zurawa-Janicka D, Narkiewicz J, Lipińska B (2007). "[Characterization of the HtrA family of proteins]". Postepy Biochem. 53 (1): 27–36. PMID 17718385.
- Maruyama K, Sugano S (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. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (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. PMID 9373149.
- Savopoulos JW, Carter PS, Turconi S, et al. (2000). "Expression, purification, and functional analysis of the human serine protease HtrA2". Protein Expr. Purif. 19 (2): 227–34. doi:10.1006/prep.2000.1240. PMID 10873535.
- Faccio L, Fusco C, Viel A, Zervos AS (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. PMID 10995577.
- Suzuki Y, Imai Y, Nakayama H, et al. (2001). "A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death". Mol. Cell 8 (3): 613–21. doi:10.1016/S1097-2765(01)00341-0. PMID 11583623.
- Verhagen AM, Silke J, Ekert PG, et al. (2002). "HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins". J. Biol. Chem. 277 (1): 445–54. doi:10.1074/jbc.M109891200. PMID 11604410.
- Hegde R, Srinivasula SM, Zhang Z, et al. (2002). "Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction". J. Biol. Chem. 277 (1): 432–8. doi:10.1074/jbc.M109721200. PMID 11606597.
- Vucic D, Deshayes K, Ackerly H, et al. (2002). "SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)". J. Biol. Chem. 277 (14): 12275–9. doi:10.1074/jbc.M112045200. PMID 11801603.
- van Loo G, van Gurp M, Depuydt B, et al. (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 Differ. 9 (1): 20–6. doi:10.1038/sj/cdd/4400970. PMID 11803371.
- Li W, Srinivasula SM, Chai J, et al. (2002). "Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi". Nat. Struct. Biol. 9 (6): 436–41. doi:10.1038/nsb795. PMID 11967569.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Yang QH, Church-Hajduk R, Ren J, et al. (2003). "Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis". Genes Dev. 17 (12): 1487–96. doi:10.1101/gad.1097903. PMC 196079. PMID 12815069. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=196079.
- Srinivasula SM, Gupta S, Datta P, et al. (2003). "Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2". J. Biol. Chem. 278 (34): 31469–72. doi:10.1074/jbc.C300240200. PMID 12835328.
- Suzuki Y, Takahashi-Niki K, Akagi T, et al. (2004). "Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways". Cell Death Differ. 11 (2): 208–16. doi:10.1038/sj.cdd.4401343. PMID 14605674.
- Okada M, Adachi S, Imai T, et al. (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. PMID 14645012.
- Park HJ, Seong YM, Choi JY, et al. (2004). "Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi". Neurosci. Lett. 357 (1): 63–7. doi:10.1016/j.neulet.2003.11.068. PMID 15036614.
- Guo Y, Cheong N, Zhang Z, et al. (2004). "Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death". J. Biol. Chem. 279 (23): 24813–25. doi:10.1074/jbc.M402049200. PMID 15044455.
External Links
- The MEROPS online database for peptidases and their inhibitors: S01.278
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PDB gallery
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1lcy: Crystal Structure of the Mitochondrial Serine Protease HtrA2
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