Structural and biological properties of the Drosophila insulin-like peptide 5 show evolutionary conservation.
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.
Receptor Systems Biology Laboratory, Insulin and Incretin Biology, Hagedorn Research Institute, 2820 Gentofte, Denmark.
Waseem
W
Sajid
Nikolaj
N
Kulahin
Gerd
G
Schluckebier
Ulla
U
Ribel
Hope Rosalind
HR
Henderson
Marc
M
Tatar
Bo Falck
BF
Hansen
Angela Manegold
AM
Svendsen
Vladislav V
VV
Kiselyov
Per
P
Nørgaard
Per-Olof
PO
Wahlund
Jakob
J
Brandt
Ronald A
RA
Kohanski
Asser Sloth
AS
Andersen
Pierre
P
De Meyts
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D007457:Iodine Radioisotopes; D050155:Lipogenesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D014199:Trehalose / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D007457:Iodine Radioisotopes; C084797:Leydig insulin-like protein; D011506:Proteins; D014199:Trehalose; D011972:Receptor, Insulin