Solution structure of the antiapoptotic protein bcl-2

The structures of two isoforms of Bcl-2 that differ by two amino acids have been determined by NMR spectroscopy. Because wildtype Bcl-2 behaved poorly in solution, the structures were determined by using Bcl-2/Bcl-x(L) chimer as in which part of the putative unstructured loop of Bcl-2 was replaced wi th a shortened loop from Bcl-x(L). These chimeric proteins have a low pi co mpared with the wild-type protein and are soluble. The structures of the tw o Bcl-2 isoforms consist of 6 alpha -helices with a hydrophobic groove on t he surface similar to that observed for the homologous protein, Bcl-x(L). C omparison of the Bcl-2 structures to that of Bcl-x(L) shows that although t he overall fold is the same, there are differences in the structural topolo gy and electrostatic potential of the binding groove. Although the structur es of the two isoforms of Bcl-2 are virtually identical, differences were o bserved in the ability of the proteins to bind to a 25-residue peptide from the proapoptotic Bad protein and a 16-residue peptide from the proapoptoti c Bak protein. These results suggest that there are subtle differences in t he hydrophobic binding groove in Bcl-2 that may translate into differences in antiapoptotic activity for the two isoforms.