Serine protease HTRA2, mitochondrial explained

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene.^{[1] [2] [3]} This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.^{[4] [5]}

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.^[6] 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.^[7]

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.^[7] 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.^[4] 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^[8] and neurodegenerative disease.^[7] Strong evidences supported of HtrA2's involvement in oncogenesis. This protein is widely expressed in a variety of cancer cell lines,^{[9] [10] [11] [12]} 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.^[5]

Interactions

HtrA serine peptidase 2 has been shown to interact with MAPK14, XIAP^{[13] [14]} and BIRC2.^{[13] [14]}

Further reading

• Zurawa-Janicka D, Narkiewicz J, Lipińska B . [Characterization of the HtrA family of proteins] . Postepy Biochemii . 53 . 1 . 27–36 . 2007 . 17718385 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Savopoulos JW, Carter PS, Turconi S, Pettman GR, Karran EH, Gray CW, Ward RV, Jenkins O, Creasy CL . Expression, purification, and functional analysis of the human serine protease HtrA2 . Protein Expression and Purification . 19 . 2 . 227–34 . Jul 2000 . 10873535 . 10.1006/prep.2000.1240 .
• Faccio L, Fusco C, Viel A, Zervos AS . Tissue-specific splicing of Omi stress-regulated endoprotease leads to an inactive protease with a modified PDZ motif . Genomics . 68 . 3 . 343–7 . Sep 2000 . 10995577 . 10.1006/geno.2000.6263 .
• Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R . A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death . Molecular Cell . 8 . 3 . 613–21 . Sep 2001 . 11583623 . 10.1016/S1097-2765(01)00341-0 . free .
• 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 . 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 . Jan 2002 . 11604410 . 10.1074/jbc.M109891200 . free .
• Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES . 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 . Jan 2002 . 11606597 . 10.1074/jbc.M109721200 . free .
• Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ, Dixit VM . SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP) . The Journal of Biological Chemistry . 277 . 14 . 12275–9 . Apr 2002 . 11801603 . 10.1074/jbc.M112045200 . free .
• van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P . 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 . Jan 2002 . 11803371 . 10.1038/sj.cdd.4400970 . free .
• Li W, Srinivasula SM, Chai J, Li P, Wu JW, Zhang Z, Alnemri ES, Shi Y . Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi . Nature Structural Biology . 9 . 6 . 436–41 . Jun 2002 . 11967569 . 10.1038/nsb795 . 21170905 .
• Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C . Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis . Genes & Development . 17 . 12 . 1487–96 . Jun 2003 . 12815069 . 196079 . 10.1101/gad.1097903 .
• Srinivasula SM, Gupta S, Datta P, Zhang Z, Hegde R, Cheong N, Fernandes-Alnemri T, Alnemri ES . Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2 . The Journal of Biological Chemistry . 278 . 34 . 31469–72 . Aug 2003 . 12835328 . 10.1074/jbc.C300240200 . free .
• Suzuki Y, Takahashi-Niki K, Akagi T, Hashikawa T, Takahashi R . Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways . Cell Death and Differentiation . 11 . 2 . 208–16 . Feb 2004 . 14605674 . 10.1038/sj.cdd.4401343 . free .
• Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T . 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 . Mar 2004 . 14645012 . 10.1182/blood-2003-05-1605 . free . 2433/145297 . free .
• Park HJ, Seong YM, Choi JY, Kang S, Rhim H . Alzheimer's disease-associated amyloid beta interacts with the human serine protease HtrA2/Omi . Neuroscience Letters . 357 . 1 . 63–7 . Feb 2004 . 15036614 . 10.1016/j.neulet.2003.11.068 . 12059062 .
• Guo Y, Cheong N, Zhang Z, De Rose R, Deng Y, Farber SA, Fernandes-Alnemri T, Alnemri ES . Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death . The Journal of Biological Chemistry . 279 . 23 . 24813–25 . Jun 2004 . 15044455 . 10.1074/jbc.M402049200 . free .

External links

• The MEROPS online database for peptidases and their inhibitors: S01.278

Notes and References

1. Faccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS . 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 . Jan 2000 . 10644717 . 10.1074/jbc.275.4.2581 . free .
2. 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 . Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response . European Journal of Biochemistry . 267 . 18 . 5699–710 . Sep 2000 . 10971580 . 10.1046/j.1432-1327.2000.01589.x . free .
3. Web site: Entrez Gene: HTRA2 HtrA serine peptidase 2.
4. Jones JM, Datta P, Srinivasula SM, Ji W, Gupta S, Zhang Z, Davies E, Hajnóczky G, Saunders TL, Van Keuren ML, Fernandes-Alnemri T, Meisler MH, Alnemri ES . Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice . Nature . 425 . 6959 . 721–7 . Oct 2003 . 14534547 . 10.1038/nature02052 . 2027.42/62561 . 4372496 . free .
5. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Müller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Krüger R . Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease . Human Molecular Genetics . 14 . 15 . 2099–111 . Aug 2005 . 15961413 . 10.1093/hmg/ddi215 . free .
6. Web site: Uniprot: O43464 - HTRA2_HUMAN.
7. Vande Walle L, Lamkanfi M, Vandenabeele P . The mitochondrial serine protease HtrA2/Omi: an overview . Cell Death and Differentiation . 15 . 3 . 453–60 . Mar 2008 . 18174901 . 10.1038/sj.cdd.4402291 . free .
8. Bulteau AL, Bayot A . Mitochondrial proteases and cancer . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1807 . 6 . 595–601 . Jun 2011 . 21194520 . 10.1016/j.bbabio.2010.12.011 . free .
9. Bowden MA, Di Nezza-Cossens LA, Jobling T, Salamonsen LA, Nie G . Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer . Gynecologic Oncology . 103 . 1 . 253–60 . Oct 2006 . 16650464 . 10.1016/j.ygyno.2006.03.006 .
10. Lee SH, Lee JW, Kim HS, Kim SY, Park WS, Kim SH, Lee JY, Yoo NJ . Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer . APMIS . 111 . 5 . 586–90 . May 2003 . 12887511 . 10.1034/j.1600-0463.2003.1110508.x. 24058023 .
11. Narkiewicz J, Klasa-Mazurkiewicz D, Zurawa-Janicka D, Skorko-Glonek J, Emerich J, Lipinska B . Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer . Clinical Biochemistry . 41 . 7–8 . 561–9 . May 2008 . 18241672 . 10.1016/j.clinbiochem.2008.01.004 .
12. Zurawa-Janicka D, Kobiela J, Stefaniak T, Wozniak A, Narkiewicz J, Wozniak M, Limon J, Lipinska B . 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 . 2008 . 10.18388/abp.2008_3123 . 18231652 . free .
13. Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES . The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein . The Journal of Biological Chemistry . 278 . 40 . 38699–706 . Oct 2003 . 12865429 . 10.1074/jbc.M303179200 . free .
14. 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 . 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 . Jan 2002 . 11604410 . 10.1074/jbc.M109891200 . free .