CHIMERIC RECEPTORS INDICATE THAT PHENYLALANINE-39 IS A MAJOR CONTRIBUTOR TO INSULIN SPECIFICITY OF THE INSULIN-RECEPTOR

The exact nature of how the insulin molecule interacts with the insuli n receptor is obscure although chimeric receptors have shown that the ligand specificity of the insulin receptor and the IGF-I receptor (i,e , the sequences that discriminate between insulin and insulinlike grow th factor I) reside in different regions of a common binding site and that the N-terminal 68 amino acids of the insulin receptor are involve d in conferring specificity for insulin on this receptor (Kjeldsen, T. , Andersen, A, S,, Wiberg, F. C,, Rasmussen, J, S,, Schaffer, L,, Bals chmidt, P,, Moller, K, B., and Moller, N, P, H. (1991) Proc, Natl. Aca d. Sci, U,S. A, 88, 4404-4408), Using chimeric insulin/IGF-I receptors to elucidate how the insulin receptor interacts with the insulin mole cule we identified phenylalanine 39 of the insulin receptor as a major contributor in determining the receptor specificity for insulin, incr easing insulin affinity 15-fold when replacing the corresponding amino acid in the insulin-like growth factor I receptor. Furthermore, repla cement of the insulin receptor amino acid phenylalanine 39 with the co rresponding IGF-I receptor amino acid, serine 35, decreased insulin af finity 8-fold.