The many, diverse apoptosis proteins found in higher organisms allow for tissue-specific mechanisms that enable the precise regulation of cell survival , whereby specific members of apoptotic gene families are expressed at certain times in development. Post-translational modifications and protein-interaction networks add further fine-tuning of life-span regulation. Yet the domains associated with the core apoptotic proteins are highly conserved throughout animal species. Domains such as CARD (IPR001315), Death (DD) (IPR000488), Death effector (DED) (IPR001875) and Dapin/Pyrin (IPR004020) act as interaction motifs that promote interactions with proteins containing the same domains, for instance CARD-CARD interactions. In this way, proteins can specifically target certain proteins within a pathway without the problem of cross-reactivity. Within a single protein, these domains can occur in combination with other interaction domains, permitting a specific sequence of events, or enabling the assembly of multi-protein complexes. For example, the Apaf-1 protein that is critical for forming the Apaf1/cyt c/caspase-9 apoptosome contains a CARD domain to bind to the CARD-containing caspase-9, a series of WD repeat domains to bind to cytochrome C, and a NB-ARC domain to allow Apaf1 to oligomerise into a heptamer. The assembly of the apoptosome provides a scaffold upon which the protease can act.
Other conserved domains that participate in apoptosis include: the nucleotide-binding NACHT (IPR007111) and NB-ARC domains (IPR002182), which provide NTPase activity and promote oligomerization; Leucine-rich repeat (LRR) domains (IPR001611), which may recognise pathogen-derived molecules; PDZ (IPR001478), WD repeat (IPR001680) and CIDE domains (IPR003508), which mediate protein-protein interactions; and the zinc-binding BIR domains (IPR001370), which occur in the inhibitor of apoptosis (IAP) proteins.
Caspases are composed of an N-terminal pro-domain that is cleaved during activation, and C-terminal catalytic and interaction domains. All caspases contain two essential caspase catalytic domains: the p10 subunit (IPR002138), and the p20 subunit (IPR001309), the latter containing the key catalytic residues cysteine and histidine. Human caspases can be divided into three groups based on their domain architecture, which are depicted below using the InterPro Domain Architecture tool:
Ø Those that only contain catalytic domains p10 and p20 are generally downstream effector caspases, such as caspases-3, -6, -7 and –14.
Ø Those that contain a tandem pair of DED (Death effector domain) domains are initiator caspases, such as caspases-8 and –10. These caspases interact with the DED domain in FADD, which is itself attached to the TNF cell surface receptor through DD-DD domain (Death domain) interactions.
Ø Those that contain a CARD domain are either initiator caspases involved in the intrinsic pathway, caspases-2 (Golgi) and –9 (mitochondria), or those involved in activating pro-inflammatory cytokines, caspases-1, -4 and –5. The CARD domains are involved in protein-protein interactions via CARD-CARD coupling.