A multimeric model for murine anti-apoptotic protein Bcl-2 and structural insights for its regulation by post-translational modification.
A monomeric model for murine antiapoptotic protein Bcl-2 was constructed by comparative modeling with the software suite MPACK (EXDIS/DIAMOD/FANTOM) using human Bcl-xL as a template. The monomeric model shows that murine Bcl-2 is an all alpha-helical protein with a central (helix 5) hydrophobic helix surrounded by amphipathic helices and an unstructured loop of 30 residues connecting helices 1 and 2. It has been previously shown that phosphorylation of Ser 70 located in this loop region regulates the anti-apoptotic activity of Bcl-2. Based on our current model, we propose that this phosphorylation may result in a conformational change that aids multimer formation. We constructed a model for the Bcl-2 homodimer based on the experimentally determined 3D structure of the Bcl-xL: Bad peptide complex. The model shows that it will require approximately a half turn in helix 2 to expose hydrophobic residues important for the formation of a multimer. Helices 5 and 6 of the monomeric subunit Bcl-2 have been proposed to form an ion-channel by associating with helices 5 and 6 of another monomeric subunit in the higher-order complex. In the multimeric model of Bcl-2, helices 5 and 6 of each subunit were placed distantly apart. From our model, we conclude that a global conformational change may be required to bring helices 5 and 6 together during ion-channel formation.
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D017124:Conserved Sequence; D019281:Dimerization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D040681:Structural Homology, Protein
D019253:Proto-Oncogene Proteins c-bcl-2