The death-fold superfamily of homotypic interaction motifs

The death-fold superfamily encompasses four structurally homologous subfamilies that engage in homotypic, subfamily-restricted interactions. The Death Domains (DDs), the Death Effector Domains (DEDs), the CAspase Recruitment Domains (CARDs) and the PYrin Domains (PYDs) constitute key building blocks involved in the assembly of multimeric complexes implicated in signaling cascades leading to inflammation and cell death. We review the molecular basis of these homotypic domain–domain interactions in light of their structure, function and evolution. In addition, we elaborate on three distinct types of asymmetric interactions that were recently identified from the crystal structures of three multimeric, death-fold complexes: the MyDDosome, the PIDDosome and the Fas/FADD-DISC. Insights into the mechanisms of interaction of death-fold domains will be useful to design strategies for specific modulation of complex formation and might lead to novel therapeutic applications.