Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex.
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.
Park
Hyun Ho
HH
Weill Medical College, Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Logette
Emmanuelle
E
Raunser
Stefan
S
Cuenin
Solange
S
Walz
Thomas
T
Tschopp
Jurg
J
Wu
Hao
H
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
D053420:CRADD Signaling Adaptor Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D053143:Caspase 2