2of5 | pdb_00002of5
Oligomeric Death Domain complex
Structural highlights
Disease[CRADD_HUMAN] Defects in CRADD are the cause of mental retardation autosomal recessive type 34 (MRT34) [MIM:614499]. A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRT34 is a non-syndromic form. Affected individuals have mildly delayed development and significantly impaired cognitive function, precluding independent living and self-care. Speech is rudimentary, but articulate; autism is not present.[1] Function[CRADD_HUMAN] Apoptotic adaptor molecule specific for caspase-2 and FASL/TNF receptor-interacting protein RIP. In the presence of RIP and TRADD, CRADD recruits caspase-2 to the TNFR-1 signalling complex. [PIDD_HUMAN] Promotes apoptosis downstream of the tumor suppressor as component of the DNA damage/stress response pathway that connects p53/TP53 to apoptosis. Associates with NEMO/IKBKG and RIP1 and enhances sumoylation and ubiquitination of NEMO/IKBKG which is important for activation of the transcription factor NF-kappa-B. Associates with CASP2/caspase-2 and CRADD/RAIDD, and induces activation of CASP2 which an important regulator in apoptotic pathways.[2] [3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedProteins 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. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex.,Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H Cell. 2007 Feb 9;128(3):533-46. PMID:17289572[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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