title: Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex.
abstract: Proteins of the death domain (DD) superfamily mediate assembly of oligomeric signaling complexes for the activation of caspases and kinases via unknown mechanisms. Here we report the crystal structure of the PIDD DD and RAIDD DD complex, which forms the core of the caspase-2-activating complex PIDDosome. Although RAIDD DD and PIDD DD are monomers, they assemble into a complex that comprises seven RAIDD DDs and five PIDD DDs. Despite the use of an asymmetric assembly mechanism, all DDs in the complex are in quasi-equivalent environments. The structure provided eight unique asymmetric interfaces, which can be classified into three types. These three types of interactions together cover a majority of the DD surface. Mutagenesis on almost all interfaces leads to disruption of the assembly, resulting in defective caspase-2 activation. The three types of interactions may represent most, if not all, modes of interactions in the DD superfamily for assembling complexes of different stoichiometry.
authors.affiliation: Weill Medical College, Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Park
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Logette
authors.forename: Stefan
authors.initials: S
authors.lastname: Raunser
authors.forename: Solange
authors.initials: S
authors.lastname: Cuenin
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D053420:CRADD Signaling Adaptor Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism; D018360:Crystallography, X-Ray; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D053420:CRADD Signaling Adaptor Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D053143:Caspase 2