6yli
From Proteopedia
Crystal structure of human bcl-xL bound to trichoplax adhaerens trBak BH3
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 PubMedIn metazoans, Bcl-2 family proteins are major regulators of mitochondrially mediated apoptosis; however, their evolution remains poorly understood. Here, we describe the molecular characterization of the four members of the Bcl-2 family in the most primitive metazoan, Trichoplax adhaerens All four trBcl-2 homologs are multimotif Bcl-2 group, with trBcl-2L1 and trBcl-2L2 being highly divergent antiapoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 are homologs of proapoptotic Bax and Bak, respectively. trBax expression permeabilizes the mitochondrial outer membrane, while trBak operates as a BH3-only sensitizer repressing antiapoptotic activities of trBcl-2L1 and trBcl-2L2. The crystal structure of a trBcl-2L2:trBak BH3 complex reveals that trBcl-2L2 uses the canonical Bcl-2 ligand binding groove to sequester trBak BH3, indicating that the structural basis for apoptosis control is conserved from T. adhaerens to mammals. Finally, we demonstrate that both trBax and trBak BH3 peptides bind selectively to human Bcl-2 homologs to sensitize cancer cells to chemotherapy treatment. Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis.,Popgeorgiev N, Sa JD, Jabbour L, Banjara S, Nguyen TTM, Akhavan-E-Sabet A, Gadet R, Ralchev N, Manon S, Hinds MG, Osigus HJ, Schierwater B, Humbert PO, Rimokh R, Gillet G, Kvansakul M Sci Adv. 2020 Sep 30;6(40):eabc4149. doi: 10.1126/sciadv.abc4149. Print 2020 Sep. PMID:32998881[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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