Molecular basis for Bcl-2 homology 3 domain recognition in the Bcl-2 protein family: identification of conserved hot spot interactions.
The proteins of the Bcl-2 family are important regulators of apoptosis, or programmed cell death. These proteins regulate this fundamental biological process via the formation of heterodimers involving both pro- and anti-apoptotic family members. Disruption of the balance between anti- and pro-apoptotic Bcl-2 proteins is the cause of numerous pathologies. Bcl-xl, an anti-apoptotic protein of this family, is known to form heterodimers with multiple pro-apoptotic proteins, such as Bad, Bim, Bak, and Bid. To elucidate the molecular basis of this recognition process, we used molecular dynamics simulations coupled with the Molecular Mechanics/Poisson-Boltzmann Surface Area approach to identify the amino acids that make significant energetic contributions to the binding free energy of four complexes formed between Bcl-xl and pro-apoptotic Bcl-2 homology 3 peptides. A fifth protein-peptide complex composed of another anti-apoptotic protein, Bcl-w, in complex with the peptide from Bim was also studied. The results identified amino acids of both the anti-apoptotic proteins as well as the Bcl-2 homology 3 (BH3) domains of the pro-apoptotic proteins that make strong, recurrent interactions in the protein complexes. The calculations show that the two anti-apoptotic proteins, Bcl-xl and Bcl-w, share a similar recognition mechanism. Our results provide insight into the molecular basis for the promiscuous nature of this molecular recognition process by members of the Bcl-2 protein family. These amino acids could be targeted in the design of new mimetics that serve as scaffolds for new antitumoral molecules.
Moroy
Gautier
G
Laboratoire de Biophysicochimie Moléculaire, Institut de Chimie, UMR 7177, Université de Strasbourg, F-67000 Strasbourg, France.
Martin
Elyette
E
Dejaegere
Annick
A
Stote
Roland H
RH
D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D003198:Computer Simulation; D017124:Conserved Sequence; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry* / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000737:chemistry* / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein