deathdomaincontaining

Death-domain-containing proteins are a class of signaling molecules that harbor a death domain (DD), a conserved protein interaction motif of about 80 amino acids. They are part of the death domain superfamily, which also includes domains such as death effector domains (DED), caspase activation and recruitment domains (CARD), and pyrin domains (PYD). Death domains promote homotypic interactions that assemble signaling complexes essential for programmed cell death and immune signaling.

The death domain adopts a six-helix bundle structure and interacts with other DD-containing proteins through defined surfaces, enabling assembly of multiprotein complexes such as the death-inducing signaling complex (DISC). In extrinsic apoptosis, for example, receptor engagement by TNF-family ligands can recruit adaptor proteins like FADD via DD–DD interactions, which in turn recruit initiator caspases to trigger caspase activation. Other DD-containing adaptors, such as TRADD and RIPK1, link death receptor signaling to apoptotic, necroptotic, or inflammatory pathways depending on cellular context and post-translational modifications.

Representative examples of death-domain-containing proteins include FADD (Fas-associated death domain protein), TRADD (TNFR1-associated death domain protein), RIPK1 (receptor-interacting serine/threonine-protein kinase 1), DAPK1 (death-associated protein kinase 1), and PIDD (p53-induced death domain protein). The presence of DDs is widespread among metazoans and contributes to the versatility of signaling networks regulating cell fate, inflammation, and immune responses. Deregulation of DD-mediated signaling has been linked to cancers, autoimmune diseases, and viral immune evasion strategies that exploit the host cell death machinery.