Death domain

The death domain (DD) is a protein interaction module composed of six alpha-helices and belongs to the death fold class. It is structurally related to the death effector domain (DED) and caspase recruitment domain (CARD), which function in similar pathways involving apoptosis and inflammation. DD-containing proteins can self-associate, forming oligomers, and are found in various combinations with other domains such as CARDs, kinase domains, or leucine-rich repeats.

In humans, eight of the 30 known TNF receptors contain DDs in their cytoplasmic tails, facilitating caspase activation and apoptosis. Other DD-containing proteins, like MyD88, are linked to innate immunity through interactions with Toll-like receptors. The DD superfamily includes four subfamilies: DD, DED, CARD, and PYD (pyrin domain), evolutionarily conserved in multicellular organisms.

Genome analysis reveals 32 DDs, 7 DEDs, 28 CARDs, and 19 PYDs in the human genome. Dysregulation of death domains is implicated in cancer through gene alterations affecting apoptosis pathways, such as overexpression of FADD or IAPs, or mutations in caspase genes. Head and neck squamous cell carcinomas frequently exhibit these alterations.

Beyond cancer, DD dysfunction contributes to diseases like autoimmune lymphoproliferative syndrome (ALPS), where Fas death domain mutations disrupt apoptotic signaling via the death inducing signaling complex (DISC). Specific mutations at A1009G and E256G in the Fas gene's intracellular DD impair apoptosis pathways, highlighting the critical role of DDs in health and disease.