BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax.
Bcl-2 was isolated from the t(14;18) chromosomal breakpoint in follicular B-cell lymphoma. Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. An emerging family of Bcl-2-related proteins share two highly conserved regions referred to here as Bcl-2 homology 1 and 2 (BH1 and BH2) domains (Fig. 1). This includes Bax which heterodimerizes with Bcl-2 and when overexpressed counteracts Bcl-2. We report here that site-specific mutagenesis of Bcl-2 establishes the two domains as novel dimerization motifs. Substitution of Gly 145 in BH1 domain or Trp 188 in BH2 domain completely abrogated Bcl-2's death-repressor activity in interleukin-3 deprivation, gamma-irradiation and glucocorticoid-induced apoptosis. Mutations that affected Bcl-2's function also disrupted its heterodimerization with Bax, yet still permitted Bcl-2 homodimerization. These results establish a functional role for the BH1 and BH2 domains and suggest Bcl-2 exerts its action through heterodimerization with Bax.
Yin
X M
XM
Division of Molecular Oncology, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110.
Oltvai
Z N
ZN
Korsmeyer
S J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001704:Biopolymers; D002999:Clone Cells; D017124:Conserved Sequence; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D001704:Biopolymers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein