Importance of the 10-13 region of glucagon for its receptor interactions and activation of adenylate cyclase.
The role of the Tyr10-Ser11-Lys12-Tyr13 region of glucagon in the binding interaction and activation of the glucagon receptor was investigated by means of the synthetic glucagon analogues [Phe13]glucagonamide, [Phe10]glucagonamide, [Phe10]glucagon, [Phe10,13]glucagon, [Pro11]glucagon, [Pro11,Gly12]glucagonamide, [Ala11]glucagon, and [Oac11-13]glucagonamide. These analogues were synthesized by solid-phase peptide synthesis on p-methylbenzhydrylamine or Merrifield resins with protected N alpha-tert-butyloxycarbonyl amino acids. Purification by dialysis, cation-exchange chromatography, gel filtration, and preparative reverse-phase high-performance liquid chromatography (HPLC) gave products that proved homogeneous by thin-layer chromatography and HPLC and on analysis by amino acid analysis, by sequencing, and by alpha-chymotryptic peptide mapping with HPLC. Biological activities were examined by measurement of the stimulation of liver plasma membrane adenylate cyclase and by specific displacement of [125I]glucagon from glucagon receptors. The results of these studies indicate that while the biological "message" region of glucagon is located elsewhere, the 10-13 region has multiple roles in the glucagon-glucagon receptor interaction: this region provides functional groups for direct binding interaction with the receptor, and this region interacts with the receptor in such a way as to allow the "transduction message" portion of glucagon to interact and activate the receptor.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002918:Chymotrypsin; D004789:Enzyme Activation; D005934:Glucagon / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018027:Receptors, Glucagon
D000596:Amino Acids; D007202:Indicators and Reagents; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018027:Receptors, Glucagon; D005934:Glucagon; D002918:Chymotrypsin; D000262:Adenylyl Cyclases