Structural and Biological Properties of the Drosophila Insulin-like Peptide 5 Show Evolutionary Conservation

• Published in: The Journal of biological chemistry 2011-01, Vol.286 (1), p.661-673
• Main Authors: Sajid, Waseem, Kulahin, Nikolaj, Schluckebier, Gerd, Ribel, Ulla, Henderson, Hope Rosalind, Tatar, Marc, Hansen, Bo Falck, Svendsen, Angela Manegold, Kiselyov, Vladislav V., Nørgaard, Per, Wahlund, Per-Olof, Brandt, Jakob, Kohanski, Ronald A., Andersen, Asser Sloth, De Meyts, Pierre
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Amino Acid Sequence; Animals; Blood Glucose - metabolism; Conserved Sequence; Crystal Structure; Crystallography, X-Ray; dilp5; Drosophila; Drosophila melanogaster; Drosophila Metabolism; Evolution, Molecular; Female; Humans; Insulin; Insulin - chemistry; Insulin - metabolism; Insulin - pharmacology; Insulin Receptor; Insulin-binding Protein; Iodine Radioisotopes; Lipogenesis - drug effects; Male; Mice; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Structure and Folding; Proteins - chemistry; Proteins - metabolism; Proteins - pharmacology; Rats; Receptor Structure-Function; Receptor, Insulin - metabolism; Receptor-tyrosine Kinase; Trehalose - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.156018

We report the crystal structure of two variants of Drosophila melanogaster insulin-like peptide 5 (DILP5) at a resolution of 1.85 Å. DILP5 shares the basic fold of the insulin peptide family (T conformation) but with a disordered B-chain C terminus. DILP5 dimerizes in the crystal and in solution. The dimer interface is not similar to that observed in vertebrates, i.e. through an anti-parallel β-sheet involving the B-chain C termini but, in contrast, is formed through an anti-parallel β-sheet involving the B-chain N termini. DILP5 binds to and activates the human insulin receptor and lowers blood glucose in rats. It also lowers trehalose levels in Drosophila. Reciprocally, human insulin binds to the Drosophila insulin receptor and induces negative cooperativity as in the human receptor. DILP5 also binds to insect insulin-binding proteins. These results show high evolutionary conservation of the insulin receptor binding properties despite divergent insulin dimerization mechanisms.