chapter  4
. Functional domains in apoptosis proteins
1. Int roduction
ByKay Hofmann
Pages 10

The first paragraph starts by introducing the domain concept, explaining the relationship between ‘structural domains’ and ‘functional domains’. The methods being used to identify homology domains and to detect their occurrence in protein sequences are briefly discussed. While functional domains are present in all major signaling pathways, they are particularly abundant in apoptotic signaling, owing to the ‘multiple-adapter’ architecture of the pathways involved. The following para­ graphs review the most commonly found domain types and discuss what is known about their modus operandi. The most upstream event of apoptosis signaling is the interaction between a death-inducing ligand and its receptor. This interaction is mediated by two particular domain types, one (TNH for TNF homology) found in the ligand, and the other one (TNFR-CRD for TNF receptor çysteine-rich domain) in the respective receptors. The death receptors relay the apoptosis signal by their cytoplasmic region containing another domain type, the ‘death domain’ (DD). The next steps involve a number of adapter proteins harboring interaction domains of the six-helix bundle superfamily, namely, death domains (DD), death effector domains (DED), caspase recruitment domains (CARD), and pyrin domains (PYD). Several of these adapter proteins branch the signaling pathway towards nonapoptotic outcomes, including NF-kB activation. The presence of TRAF domains or Toll/IL-IR domain (TIR) is a hallmark of those proteins. Eventually, the recruitment of the death adapter proteins leads to the activation of caspases, a class of proteases specifically cleaving a number of substrates, including other

caspases. A prominent class of physiologic caspase inhibitors containing the ‘BIR’ domain adds another level of regulation.