Genetics of Apoptosis

5.

Other important domains

The domains discussed in the previous sections serve to initiate an apoptosis signal
and to relay it to the initiator caspases. The following paragraphs deal with some
important domain families working further downstream in the apoptosis pathway.

5.1

The Bcl-2 motif family

It has been known for a long time that the product of the Bcl-2 oncogene plays an
important role in negatively regulating apoptosis. Soon, a large family of Bcl-2 related
proteins was identified, some members of which apparently act in a proapoptotic
way, while others resemble bcl-2 in its antiapoptotic effect (reviewed in Chao and
Korsmeyer, 1998; Gross et al., 1999; Adams and Cory, 2001). A hall-mark of the
Bcl-2 relatives is the presence of three particularly well-conserved sequence motifs
known as the BH1, BH2, and BH3 regions (Bcl-2 homology). Occasionally, these
regions are also referred to as BH domains, but this name should be avoided since
they are certainly not domains by any definition. The BH regions are just patches of
relatively high conservation contained in an α-helical context, as can be seen from
the three-dimensional structure of several Bcl-2 homologs (Muchmore et al., 1996;
Chou et al., 1999; McDonnell et al., 1999).
Structurally and functionally, the members of the Bcl-2 family (Table 8) can be
subdivided into at least three different classes. The first class has an overall similarity
to Bcl-2, typically carries a C-terminal membrane anchor, and has an antiapoptotic
function. Many members of this class also contain an N-terminal extension of the
Bcl-2 homology, the so-called BH4 region. The second class groups proapoptotic
proteins with overall Bcl-2 similarity. Most of these proteins carry BH1–3 regions
but lack the BH4 region. This lack of BH4 conservation has been proposed as a
distinction between pro- and antiapoptotic family members (Adams and Cory, 2001),
but the trend is not absolute since the proapoptotic Bok protein contains a
recognizable BH4 motif (Hsu, S.Y. et al., 1997). A third class of Bcl-2-related proteins
is very heterogeneous and groups several proteins where only sequence of the BH3
region is conserved; all members of this class appear to be proapoptotic. As more
structures of Bcl-2 relatives become available, it will most likely be appropriate to
subdivide this latter class into proteins with Bcl-2 related folds, which have lost
conservation in the BH1 and BH2 regions, and proteins unrelated to Bcl-2, which
have adopted a sequence motif related to the BH3 region. An obvious example of the
former subgroup is the BH3-only protein Bid, whose structure can clearly be
superimposed on that of all-BH proteins (Chou et al., 1999; McDonnell et al., 1999).
For the latter subgroup, no structures are available, but Hrk appears to be a good
candidate, as the sequence is far too short to fit into the Bcl-2 fold.
As mentioned before, the structure of the Bcl-2 family is monolithic and does not
contain domains. It consists of two central hydrophobic helices, which are surrounded

FUNCTIONAL DOMAINS IN APOPTOSIS PROTEINS 91