architecture are shown in Figure 2. The N-terminus of the proteins is occupied by
an adapter-type domain, which can be either CARD, PYD, TIR, or BIR. The central
part of the proteins consists of a NTPase domain, either of the NB-ARC or the
NACHT type, while the C-terminal part consists of a variable number of repeats,
typically of the WD-40 repeat or leucine-rich repeat (LRR) type. An attempt to infer
the function of these protein from the known properties of the constituting domains
gives only a rough idea: WD-40 and LRR domains are generic protein interaction
domains, which bind to a wide variety of other proteins. NB-ARC and NACHT
domains are NTPases, possibly ATPases, of unknown function. Generally, NTPases
are involved in reactions that require energy, includingfolding/unfolding of proteins,
DNA, or RNA. The best understood part is the N-terminal adapter domain, which
most likely mediates the recruitment of another protein of the same domain type,
frequently with the purpose of eventually inducing proximity of some catalytically
active component. It can, however, not be predicted whether these three-domain
proteins are recruiting something, or if they are being recruited to a complex.
APAF1 is the only protein of this architecture for which the mode of action is
reasonably well understood. The WD-40 repeat portion is thought to bind
cytochrome c released from mitochondrial stores. This binding must trigger a change
in conformation that allows the formation of the apoptosome, recruiting and
activating caspase-9 by its N-terminal CARD domain. The role of the NB-ARC
domain in this process is not understood—it might be involved in facilitating the
Figure 2. Representative domain architectures of several three-domain apoptosis regulators.
The domain abbreviations are CARD, caspase recruitment domain; NB-ARC, ATPase
domain; TIR, Toll/IL-1R type domain; LRR, leucine-rich repeat domain; PYD, pyrin domain;
and B, BIR domain.
FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 95