Islet neogenesis associated protein (ingap): Structural and dynamical properties of its active pentadecapeptide

Abstract: We have studied the structural and dynamical properties of the biologically active pentadecapeptide of the islet neogenesis associated protein (INGAP-PP) and of two other pentadecapeptides with the same aminoacid composition but randomly scrambled primary sequences, using molecular dynamic simulations. Our data demonstrates that whilst the peptides with scrambled sequences show no definite prevalent structure in solution, INGAP-PP maintains a notably stable tertiary fold, namely, a conformer with a central β-sheet and closed C-terminal. Such structure resembles the one corresponding to the aminoacid sequence of human pancreatitis associated protein-1 (PAP-1), which presents 85% sequence homology with INGAP. These results could reasonably explain why the two scrambled sequences tested showed no biological activity, while INGAP-PP significantly increases β-cells function and mass both in vitro and in vivo conditions. The capability of INGAP-PP to temporarily adopt other closely related conformations offers also a plausible explanation for the 50 fold experimental difference in potency between the active pentadecapepide and the whole protein. They also suggest that the C-terminal region of INGAP-PP may plausibly be the locus for its interaction with the cell receptor. Consequently, the knowledge gathered through our data can help to obtain more potent INGAP-PP analogs, suitable for the prevention and treatment of diabetes. [Copyright &y& Elsevier]