Context-dependent Bcl-2/Bak interactions regulate lymphoid cell apoptosis.
The release of cytochrome c from mitochondria, which leads to activation of the intrinsic apoptotic pathway, is regulated by interactions of Bax and Bak with antiapoptotic Bcl-2 family members. The factors that regulate these interactions are, at the present time, incompletely understood. Recent studies showing preferences in binding between synthetic Bcl-2 homology domain 3 and antiapoptotic Bcl-2 family members in vitro have suggested that the antiapoptotic proteins Mcl-1 and Bcl-x(L), but not Bcl-2, restrain proapoptotic Bak from inducing mitochondrial membrane permeabilization and apoptosis. Here we show that Bak protein has a much higher affinity than the 26-amino acid Bak Bcl-2 homology domain 3 for Bcl-2, that some naturally occurring Bcl-2 allelic variants have an affinity for full-length Bak that is only 3-fold lower than that of Mcl-1, and that endogenous levels of these Bcl-2 variants (which are as much as 40-fold more abundant than Mcl-1) restrain part of the Bak in intact lymphoid cells. In addition, we demonstrate that Bcl-2 variants can, depending on their affinity for Bak, substitute for Mcl-1 in protecting cells. Thus, the ability of Bcl-2 to protect cells from activated Bak depends on two important contextual variables, the identity of the Bcl-2 present and the amount expressed.
Dai
Haiming
H
Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
Meng
X Wei
XW
Lee
Sun-Hee
SH
Schneider
Paula A
PA
Kaufmann
Scott H
SH
D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology* / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein