β-Sheet Models for the Ordered Filamentous Structure Formed by a Peptide That Enhances the Action of Insulin

Certain peptides with sequences related to part of the major histocompatibility complex class I antigen enhance the action of insulin. These peptides also aggregate into fibrous structures that seem to be related to their biological activity. In the current study, the 17-residue peptide with amino acid sequence Gly-Asn-Glu-Gln-Ser-Phe-Arg-Val-Asp-Leu-Arg-Thr-Leu-Leu-Arg-Tyr-Ala is used as a representative example of these bioactive molecules. As seen by electron microscopy, the peptide associates into gently twisted ribbons, 50 Å thick, in which the amount of twist decreases as the ribbons become wider. X-ray diffraction analysis suggests that the peptides are arranged as in an antiparallel β-sheet extending essentially endlessly along the fiber axis. The amino acid sequence of the peptide is such that one side of the β-sheet is predominantly polar while the opposite side is nonpolar. This allows the β-sheets to form multilayers with alternating hydrophobic and hydrophilic interfaces. The length of the extended peptide (≈54 Å) determines the thickness of the ribbon and the tendency of individual β-sheets to twist accounts for the twisting of the ribbons. An alternative model is also discussed, again based on antiparallel β-sheets, but with adjacent sheets interdigitated in a “side-by-side” fashion rather than forming stacked layers. Comparable inactive peptides such as Gly-Asn-Glu-Gln-Ser- A_l_a_-Arg-Val-Asp-Leu-Arg-Thr-Leu-Leu-Arg-Tyr-T_y_r_ (changed amino acids underlined) do not form ordered filamentous structures.