Structure of the BH3 Domains from the p53-Inducible BH3-Only Proteins Noxa and Puma in Complex with Mcl-1

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

“…The four signature hydrophobic residues of the Bak BH3 domain are buried within the groove (Fig. S5B), as in all previously determined BH3:prosurvival protein complexes (2)(3)(4)(5)27), and a salt bridge between a critical aspartyl residue on the peptide and an arginyl residue on the BH1 domain of the prosurvival protein, is also evident (Fig. S5C).…”

“…This structure we propose for the schistosome pathway is supported by biochemical data showing prosurvival and proapoptotic members bind one another with nanomolar affinity, similar to that observed for pro-and antiapoptotic Bcl-2 family members in the human pathway (28), and agrees entirely with functional predictions based on phylogenetic analysis of the protein sequences (at least for sjA and sjB). Finally, the sjA:BakBH3 crystal structure provides definitive evidence that sjA exerts its prosurvival function in exactly the same manner as mammalian (and indeed nematode) prosurvival proteins by engaging BH3 sequences within a well-defined ligand binding groove (2)(3)(4)(5)32). In addition to the proteins characterized here, other Bcl-2-related proteins (based on sequence similarity) we identified in S. japonicum and S. mansoni (Fig.…”

“…Members of the Bcl-2 protein family contain at least one of four conserved sequence motifs known as Bcl-2 homology domains (BH1-BH4). Interactions between the different factions of the Bcl-2 family are mediated by the BH3 domains of the proapoptotic proteins, which engage a hydrophobic groove on the surface of the prosurvival molecules (2)(3)(4)(5).…”

The Functional Differences between Pro-survival and Pro-apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (BH3) Domains

“…Based on previous mutagenesis studies (12,14,19,25), we predicted that two major differences at the h1 ϩ 1 and h3 positions (Fig. 1A) in most of the pro-survival versus pro-apoptotic sequences could impact their binding affinity for pro-survival proteins.…”

“…Interactions between pro-survival and pro-apoptotic proteins are mediated by the BH3 domain on the pro-apoptotic protein (Bax/Bak or BH3-only) binding into a large hydrophobic groove on the pro-survival protein (11)(12)(13)(14)(15)(16)(17). The BH3 domains of Bax and Bak also mediate homodimerization (and possibly heterodimerization) between Bax and Bak molecules (18 -22).…”