8iqk
Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival proteins
Structural highlights
FunctionB2CL1_HUMAN Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.[1] [2] Isoform Bcl-X(S) promotes apoptosis.[3] [4] Publication Abstract from PubMedThe apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival Bcl-2 family proteins act as cell guardians and protect cells against death. Selective binding and neutralization of BH3-only proteins with pro-survival Bcl-2 family proteins is critical for initiating apoptosis. In this study, the binding assay shows that the BH3 peptide derived from the BH3-only protein Bmf has a high affinity for the pro-survival proteins Bcl-2 and Bcl-xL, but a much lower affinity for Mcl-1. The complex structures of Bmf BH3 with Bcl-2, Bcl-xL and Mcl-1 reveal that the alpha-helical Bmf BH3 accommodates into the canonical groove of these pro-survival proteins, but the conformational changes and some interactions are different among the three complexes. Bmf BH3 forms conserved hydrophobic and salt bridge interactions with Bcl-2 and Bcl-xL, and also establishes several hydrogen bonds to support their binding. However, the highly conserved Asp-Arg salt bridge is not formed in the Mcl-1/Bmf BH3 complex, and few hydrogen bonds are observed. Furthermore, mutational analysis shows that substitutions of less-conserved residues in the alpha2-alpha3 region of these pro-survival Bcl-2 family proteins, as well as the highly conserved Arg, lead to significant changes in their binding affinity to Bmf BH3, while substitutions of less-conserved residues in Bmf BH3 have a more dramatic effect on its affinity to Mcl-1. This study provides structural insight into the specificity and interaction mechanism of Bmf BH3 binding to pro-survival Bcl-2 family proteins, and helps guide the design of BH3 mimics targeting pro-survival Bcl-2 family proteins. Structural basis of the specificity and interaction mechanism of Bmf binding to pro-survival Bcl-2 family proteins.,Wang H, Guo M, Wei H, Chen Y Comput Struct Biotechnol J. 2023 Jul 21;21:3760-3767. doi: , 10.1016/j.csbj.2023.07.017. eCollection 2023. PMID:37560128[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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