Abstract
HtrA2/Omi, a mitochondrial serine protease in mammals, is important in programmed cell death. However, the underlining mechanism of HtrA2/Omi-mediated apoptosis remains unclear. Analogous to the bacterial homolog HtrA (DegP), the mature HtrA2 protein contains a central serine protease domain and a C-terminal PDZ domain. The 2.0 Å crystal structure of HtrA2/Omi reveals the formation of a pyramid-shaped homotrimer mediated exclusively by the serine protease domains. The peptide-binding pocket of the PDZ domain is buried in the intimate interface between the PDZ and the protease domains. Mutational analysis reveals that the monomeric HtrA2/Omi mutants are unable to induce cell death and are deficient in protease activity. The PDZ domain modulates HtrA2/Omi-mediated cell death activity by regulating its serine protease activity. These structural and biochemical observations provide an important framework for deciphering the mechanisms of HtrA2/Omi-mediated apoptosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Horvitz, H.R. Cancer Res. 59, 1701–1706 (1999).
Jacobson, M.D., Weil, M. & Raff, M.C. Cell 88, 347–354 (1997).
Wang, X. Genes Dev. 15, 2922–2933 (2001).
Green, D.R. & Reed, J.C. Science 281, 1309–1312 (1998).
Du, C., Fang, M., Li, Y. & Wang, X. Cell 102, 33–42 (2000).
Verhagen, A.M. et al. Cell 102, 43–53 (2000).
Shi, Y. Mol. Cell 9, 459–470 (2002).
Wu, G. et al. Nature 408, 1008–1012 (2000).
Liu, Z. et al. Nature 408, 1004–1008 (2000).
Shi, Y. Cell Death Differ. 9, 93–95 (2002).
Suzuki, Y. et al. Mol. Cell 8, 613–621 (2001).
Hedge, R. et al. J. Biol. Chem. 277, 432–438 (2002).
Verhagen, A.M. et al. J. Biol. Chem. 277, 445–454 (2002).
Martin, L.M. et al. J. Biol. Chem. 277, 439–444 (2002).
van Loo, G. et al. Cell Death Differ. 9, 20–26 (2002).
Liao, D.L., Qian, J., Chisholm, D.A., Jordan, D.B. & Diner, B.A. Nature Struct. Biol. 7, 749–753 (2000).
Pallen, M.J. & Wren, B.W. Mol. Microbiol. 26, 209–221 (1997).
Harris, B.Z. & Lim, W.A. J. Cell Sci. 114, 3219–3231 (2001).
Faccio, L. et al. J. Biol. Chem. 275, 2581–2588 (2000).
Chai, J. et al. Nature 406, 855–862 (2000).
Thornberry, N.A. & Lazebnik, Y. Science 281, 1312–1316 (1998).
Srinivasula, S.M. et al. Curr. Biol. 12, 125–130 (2002).
Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M. & Clausen, T. Nature 416, 455–459 (2002).
Qin, H. et al. Nature 399, 547–555 (1999).
Chai, J. et al. Cell 104, 769–780 (2001).
Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).
Terwilliger, T.C. & Berendzen, J. Acta Crystallogr. D. 52, 749–757 (1996).
Collaborative Computational Project, Number 4. Acta Crystallogr. D 50, 760–763 (1994).
Jones, T.A., Zou, J.-Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).
Brünger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).
Schultz, J. et al. Nature Struct. Biol. 5, 19–24 (1998).
Thompson, J.D., Higgins, D.G. & Gibson, T.J. Nucleic Acids Res. 22, 4673–4680 (1994).
Acknowledgements
This research was supported by NIH grants (Y.S. and E.A.). S.M.S. is a special fellow of the Leukemia and Lymphoma Society. Y.S. is a Searle Scholar and a Rita Allen Foundation Scholar.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Li, W., Srinivasula, S., Chai, J. et al. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat Struct Mol Biol 9, 436–441 (2002). https://doi.org/10.1038/nsb795
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nsb795
This article is cited by
-
Protease-independent control of parthanatos by HtrA2/Omi
Cellular and Molecular Life Sciences (2023)
-
Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration
Nature Communications (2022)
-
Evolution of caspase-mediated cell death and differentiation: twins separated at birth
Cell Death & Differentiation (2017)
-
Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2
Cell Death & Disease (2017)
-
The crystal structure of Deg9 reveals a novel octameric-type HtrA protease
Nature Plants (2017)