Figure 3. The protein domain structure of the Bcl-2 proteins.
The Bcl-2 proteins contain up to four highly conserved domains, referred to as
Bcl-2 homology domains or BH domains (BH1–4). In addition, some of the
proteins contain a hydrophobic C-terminal domain (HCD). The positions of the
α-helixes are indicated.
The family members have either anti—or proapoptotic activity. The antiapoptotic
proteins, such as Bcl-2 and Bcl-XL, contain all four conserved domains (BH1– 4) as
well as the hydrophobic C-terminal domain. Although both Bcl-2 and Bcl-XL contain
the C-terminal hydrophobic domain, their intracellular localizations differ. Bcl-2 is
exclusively found in intracellular membranes, including the outer mitochondrial
membrane, the ER, and the nuclear envelope (Krajewski et al., 1993). In contrast, in
addition to membrane localization, Bcl-XL is also found as a soluble form in the
cytosol (Hsu, Y.T. et al., 1997). Translocation of the protein from the cytosol to the
mitochondria was found during apoptosis. This indicates that the protein can exist
in different conformations, favoring a soluble or a membrane-inserted protein form.
In addition to Bcl-2 and Bcl-XL, less well-characterized family members with
antiapoptotic activity have been identified (Figure 2).
The proapoptotic subfamily can be further divided into two groups, the
multidomain proteins, including Bax and Bak, and the ‘BH3-domain-only’ proteins,
such as Bid and Bad. The multidomain proteins all contain the BH1–3 domains and
the C-terminal hydrophobic domain, with the exception of Bcl-Xs, which, in addition
to the C-terminal domain, contains only the BH3 and BH4 domains. Although Bax
and Bak contain the same conserved domains, their subcellular localization is totally
different. Whereas Bak is inserted into the outer mitochondrial membrane in normal
cells, Bax is found predominantly in the cytosol as a soluble monomeric protein or,
to a low extent, is loosely associated with the mitochondria (Hsu and Youle, 1998;
Eskes et al., 2000). Upon apoptotic stimulation, Bax undergoes conformational
changes accompanied by a translocation of the protein form the cytosol to the
mitochondria, where it is inserted into the outer mitochondrial membrane (Wolter
et al., 1997; Goping et al., 1998; Antonsson et al., 2001).
The ‘BH3-domain-only’ proteins are a more heterogeneous group. However, the
common feature is that they possess only the BH3 domain. In addition, some of the
members contain a C-terminal hydrophobic domain, whereas others, such as Bid and
Bad, do not. The ‘BH3-domain-only’ proteins, at least partly, execute their
proapoptotic function through activation of the multidomain proteins. The best-
studied example is Bid, which will be discussed in more detail below. Bad promotes
activation of the multidomain proteins in an indirect way, by sequestering the
antiapoptotic proteins Bcl-2 or Bcl-XL; this prevents them from binding to the
multidomain proteins and inhibits their activation (Zha et al., 1997).
126 GENETICS OF APOPTOSIS