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Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi

Nature Structural Biology volume 9, pages 436–441 (2002)Cite this article

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.

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Figure 1: Structure of HtrA2/Omi.
Figure 2: HtrA2/Omi forms a pyramid-shaped homotrimer.
Figure 3: Formation of a HtrA2/Omi trimer is indispensable to its function.
Figure 4: The PDZ domain regulates the serine protease activity and the pro-apoptotic function of HtrA2/Omi.

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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.

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Authors and Affiliations

  1. Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, 08544, New Jersey, USA

    Wenyu Li, Jijie Chai, Pingwei Li, Jia-Wei Wu & Yigong Shi

  2. Kimmel Cancer Center, 233 South 10th Street

    Srinivasa M. Srinivasula, ZhiJia Zhang & Emad S. Alnemri

  3. Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, USA

    Srinivasa M. Srinivasula, ZhiJia Zhang & Emad S. Alnemri

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  1. Wenyu Li
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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

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