Genetics of Apoptosis

Mutational studies of Bcl-2 and Bcl-xL have directed attention to the hydrophobic
cleft bordered by α-helices 2–5 and 7–8 (including BH1–3 domains) (Tables^3 and
4). Single amino-acid substitutions in BH1 (Gly^145 Ala in Bcl-2; Gly^138 Al a and
Arg^139 Gln in Bcl-xL) and BH2 (Trp^188 Ala in Bcl-2) disabling antiapoptotic function
occur at known contact sites for proapoptotic BH3 domain peptides and disrupt
heterodimerization with proapoptotic BH proteins. However, not all of the residues
with strong loss of function and heterodimerization mutant phenotypes are directly
involved in BH3 peptide binding (e.g., Val^15 Glu in Bcl-2), and not all mutations
that block heterodimerization result in strong LOF phenotypes (e.g., Val^126 Gly in
Bcl-xL). Most of the single residues necessary for antiapoptotic functions of these
proteins are involved in interior contacts, both inter- and intrahelical. These
interactions involve hydrogen bonds between a central hydrophobic helix and a
peripheral helix, that is, α5 and α4 (Arg^146 : Leu^137 in Bcl-xL), and van der Waals
contacts between α1 and α5 (Val^15 : Phe^151 in Bcl-2), and α6 and α5 (Trp^188 : Tr^ p

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Table 3. Mutational studies of Bcl-2

LOF: loss of function; GOF: gain of function; GODF; gain of death function.

60 GENETICS OF APOPTOSIS