title: Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi.
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.
authors.affiliation: Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Li
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
authors.forename: Jijie
authors.initials: J
authors.lastname: Chai
authors.forename: Pingwei
authors.initials: P
authors.lastname: Li
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: ZhiJia
authors.initials: Z
authors.lastname: Zhang
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases