Genetics of Apoptosis

Shortly after the discovery of the NB-ARC ATPases, a related domain family was
described, which tends to occur in a similar set of proteins and at a similar position.
This domain family was called NACHT domain (Koonin and Aravind, 2000).
NACHT domains are found in several CARD proteins, where they are embedded
between the CARD and a C-terminal LRR region. A NACHT domain is also found
in the central region of the IAP-type protein NAIP and in the telom-erase-associated
protein TP1. The 400-residue NACHT domain has overall similarity to the NB-ARC
domain. It, too, encodes a putative NTPase and has the Walker-A and -B motifs well
conserved. At least one NACHT protein, the Het-E1 gene product from the fungus
Podospora, has been shown to bind GTP instead of ATP (Espagne et al., 1997). This
finding might point towards a function of the NACHT domain as GTPases.

6.

A domain-centric view of apoptosis

As has been demonstrated in the previous paragraphs, most proteins involved in
apoptotic signaling share specific domains belonging to a relatively small number of
domain families. While, at first glance, the domain arrangement might appear almost
random, there are nevertheless a number of recurrent domain architectures observed
in different branches of apoptotic and inflammatory pathways.
A first example of a common domain architecture with variable domain types are
the caspases, which play a central role in various branches of the apoptosis pathway.
They are translated as mostly inactive zymogens that need to be activated by
proteolysis—a process that apparently can be stimulated efficiently by bringing two
procaspases into close contact (Muzio et al., 1998; Salvesen and Dixit, 1999). This
‘induced proximity’ can be caused by a number of different interaction domains:
mammals have two caspases with an N-terminal DED (Casp-8 and -10), which are
recruited by a DED adapter protein (FADD). Another type of caspase (at least seven
mammalian enzymes) uses the CARD domain instead, which is recruited by a CARD
adapter protein (RAIDD, APAF1). In the zebrafish, at least one caspase with an N-
terminal PYD is found. While the recruitment mode of this enzyme is not yet known,
it is safe to assume that the corresponding adapter protein will also contain a pyrin
domain. Therefore, in the organisms studied to date, at least three different domain
types with similar properties are combined with the caspase catalytic domain and
serve a common purpose—the recruitment of two or more caspase molecules into an
activation complex.
A second example of a conserved meta-architecture is the two-domain adapter
proteins, which are being used to change from one ‘interaction mode’ to another one.
FADD changes from a DD-mediated interaction to a DED type, RAIDD switches
from DD to CARD, and MyD88 switches from TIR to a DD. The adapter protein
ASC/Pycard is not understood well enough to judge the direction of signaling, but
it most likely connects a PYD interaction with a CARD interaction.
A third type of multidomain architecture is particularly frequent, although detailed
knowledge about the purpose is still lacking. Some examples of this three-domain

94 GENETICS OF APOPTOSIS