Antiapoptotic Bcl-2 homolog CED-9 in Caenorhabditis elegans: dynamics of BH3 and CED-4 binding regions and comparison with mammalian antiapoptotic Bcl-2 proteins.
Proteins belonging to Bcl-2 family regulate intrinsic cell death pathway. Although mammalian antiapoptotic Bcl-2 members interact with multiple proapoptotic proteins, the Caenorhabditis elegans Bcl-2 homolog CED-9 is known to have only two proapoptotic partners. The BH3-motif of proapoptotic proteins bind to the hydrophobic groove of prosurvival proteins formed by the Bcl-2 helical fold. CED-9 is also known to interact with CED-4, a homolog of the human cell death activator Apaf1. We have performed molecular dynamics simulations of CED-9 in two forms and compared the results with those of mammalian counterparts Bcl-XL, Bcl-w, and Bcl-2. Our studies demonstrate that the region forming the hydrophobic cleft is more flexible compared with the CED-4-binding region, and this is generally true for all antiapoptotic Bcl-2 proteins studied. CED-9 is the most stable protein during simulations and its hydrophobic pocket is relatively rigid explaining the absence of functional redundancy in CED-9. The BH3-binding region of Bcl-2 is less flexible among the mammalian proteins and this lends support to the studies that Bcl-2 binds to less number of BH3 peptides with high affinity. The C-terminal helix of CED-9 lost its helical character because of a large number of charged residues. We speculate that this region probably plays a role in intracellular localization of CED-9. The BH4-motif accessibility in CED-9 and Bcl-w is controlled by the loop connecting the first two helices. Although CED-9 adopts the same Bcl-2 fold, our studies highlight important differences in the dynamic behavior of CED-9 and mammalian antiapoptotic homologs.
Department of Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, India.
Vivek
V
Modi
Ramasubbu
R
Sankararamakrishnan
D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D040681:Structural Homology, Protein
D029742:Caenorhabditis elegans Proteins; C087233:Ced-9 protein, C elegans; D019253:Proto-Oncogene Proteins c-bcl-2
accessible surface area; comparative simulations; flexible and rigid binding regions; helix bundle protein; hydrophobic binding groove; interhelical angle; programmed cell death; protein-protein interactions in apoptosis