Biology:HtrA serine peptidase 2

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Short description: Enzyme found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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,[1] XIAP[13][14] and BIRC2.[13][14]

References

  1. ↑ 1.0 1.1 "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. doi:10.1074/jbc.275.4.2581. PMID 10644717. 
  2. ↑ "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. doi:10.1046/j.1432-1327.2000.01589.x. PMID 10971580. 
  3. ↑ "Entrez Gene: HTRA2 HtrA serine peptidase 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27429. 
  4. ↑ 4.0 4.1 "Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice". Nature 425 (6959): 721–7. Oct 2003. doi:10.1038/nature02052. PMID 14534547. https://deepblue.lib.umich.edu/bitstream/2027.42/62561/1/nature02052.pdf. 
  5. ↑ 5.0 5.1 "Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease". Human Molecular Genetics 14 (15): 2099–111. Aug 2005. doi:10.1093/hmg/ddi215. PMID 15961413. 
  6. ↑ "Uniprot: O43464 - HTRA2_HUMAN". https://www.uniprot.org/uniprot/O43464. 
  7. ↑ 7.0 7.1 7.2 "The mitochondrial serine protease HtrA2/Omi: an overview". Cell Death and Differentiation 15 (3): 453–60. Mar 2008. doi:10.1038/sj.cdd.4402291. PMID 18174901. 
  8. ↑ "Mitochondrial proteases and cancer". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1807 (6): 595–601. Jun 2011. doi:10.1016/j.bbabio.2010.12.011. PMID 21194520. 
  9. ↑ "Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer". Gynecologic Oncology 103 (1): 253–60. Oct 2006. doi:10.1016/j.ygyno.2006.03.006. PMID 16650464. 
  10. ↑ "Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer". APMIS 111 (5): 586–90. May 2003. doi:10.1034/j.1600-0463.2003.1110508.x. PMID 12887511. 
  11. ↑ "Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer". Clinical Biochemistry 41 (7–8): 561–9. May 2008. doi:10.1016/j.clinbiochem.2008.01.004. PMID 18241672. 
  12. ↑ "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. doi:10.18388/abp.2008_3123. PMID 18231652. 
  13. ↑ 13.0 13.1 "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. doi:10.1074/jbc.M303179200. PMID 12865429. 
  14. ↑ 14.0 14.1 "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. doi:10.1074/jbc.M109891200. PMID 11604410. 

Further reading

External links

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



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