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Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi
Wenyu Li1, Srinivasa M Srinivasula, Jijie Chai
1Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
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 A 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.
Insights
The mitochondrial protease HtrA2/Omi
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- HtrA2/Omi is a mitochondrial serine protease crucial for programmed cell death.
- The precise mechanism of HtrA2/Omi-induced apoptosis is not fully understood.
- HtrA2/Omi shares structural homology with bacterial HtrA (DegP), featuring protease and PDZ domains.
Purpose of the Study:
- To elucidate the structural basis and mechanism of HtrA2/Omi in apoptosis.
- To investigate the role of its structural domains in protease activity and cell death induction.
Main Methods:
- X-ray crystallography to determine the 2.0 Å structure of HtrA2/Omi.
- Biochemical assays to assess protease activity.
- Mutational analysis to evaluate the function of HtrA2/Omi mutants.
Main Results:
- The crystal structure reveals a pyramid-shaped homotrimer formed by serine protease domains.
- The PDZ domain's peptide-binding pocket is sequestered at the interface with the protease domain.
- Monomeric HtrA2/Omi mutants exhibit loss of cell death induction and protease activity.
- The PDZ domain regulates HtrA2/Omi's serine protease activity, influencing apoptosis.
Conclusions:
- The homotrimeric structure of HtrA2/Omi is essential for its function in apoptosis.
- The PDZ domain plays a regulatory role in HtrA2/Omi-mediated cell death via protease activity modulation.
- These findings offer a structural and mechanistic framework for understanding HtrA2/Omi's role in apoptosis.