CONFORMATION OF THE TRANSMEMBRANE DOMAIN OF THE C-ERBB-2 ONCOGENE-ENCODED PROTEIN IN ITS MONOMERIC AND DIMERIC STATES

The human c-erbB-2 oncogene is homologous to the rat neu oncogene, bot h encoding transmembrane growth factor receptors. Overexpression and p oint mutations in the transmembrane domain of the encoded proteins in both cases have been implicated in cell transformation and carcinogene sis. In the case of the neu protein, it has been proposed that these e ffects are mediated by conformational preferences for an alpha-helix i n the transmembrane domain, which facilitates receptor dimerization, a n important step in the signal transduction process. To examine whethe r this is the case for c-erbB-2 as well, we have used conformational e nergy analysis to determine the preferred three-dimensional structures for the transmembrane domain of the c-erbB-2 protein from residues 65 0 to 668 with Val (nontransforming) and Glu (transforming) at position 659. The global minimum energy conformation for the Val-659 peptide f rom the normal, nontransforming protein was found to contain several b ends, whereas the global minimum energy conformation for Glu-659 pepti de from the mutant, transforming protein was found to be alpha-helical . Thus, the difference in conformational preferences for these transme mbrane domains may explain the difference in transforming ability of t hese proteins. The presence of higher-energy alpha-helical conformatio ns for the transmembrane domain from the normal Val-659 protein may pr ovide an explanation for the presence of a transforming effect from ov erexpression of c-erbB-2. In addition, docking of the oncogenic sequen ces in their alpha-helical and bend conformations shows that the all-a lpha-helical dimer is clearly favored energetically over the bend dime r.