title: Crystal structure of the death effector domains of caspase-8.
abstract: Caspase-8 is a key mediator in various biological processes such as apoptosis, necroptosis, inflammation, T/B cells activation, and cell motility. Caspase-8 is characterized by the N-terminal tandem death effector domains (DEDs) and the C-terminal catalytic protease domain. The DEDs mediate diverse functions of caspase-8 through homotypic interactions of the DEDs between caspase-8 and its partner proteins. Here, we report the first crystal structure of the DEDs of caspase-8. The overall structure of the DEDs of caspase-8 is similar to that of the DEDs of vFLIP MC159, which is composed of two tandem death effector domains that closely associate with each other in a head-to-tail manner. Structural analysis reveals distinct differences in the region connecting helices α2b and α4b in the second DED of the DEDs between caspase-8 and MC159, in which the helix α3b in MC159 is replaced by a loop in caspase-8. Moreover, the different amino acids in this region might confer the distinct features of solubility and aggregation for the DEDs of caspase-8 and MC159.
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yue
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Pei
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Laboratory for Computational Chemistry & Drug Design, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: tau@pku.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China. Electronic address: quanjm@pkusz.edu.cn.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Quan
mesh_terms: D000595:Amino Acid Sequence; D053181:Caspase 8 / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008976:Molluscum Contagiosum / Q000821:virology; D008977:Molluscum contagiosum virus / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D014764:Viral Proteins; C509979:viral FLIP protein, Molluscum contagiosum virus; D053181:Caspase 8
keywords: Apoptosis; Caspase-8; Death effector domain; Inflammation; Necroptosis