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

MC CARTHY, AN; MOGILNER, IG; J. RAUL GRIGERA; BORELLI, M.I.; DEL ZOTTO, H.; GAGLIARDINO, J.J.

Journal of Molecular Graphics and Modelling

Elsevier

Año: 2009 vol. 27 p. 701 - 705

1093-3263

AB S T R A C TWe have studied the structural and dynamical properties of the biologically active pentadecapeptide ofthe islet neogenesis associated protein (INGAP-PP) and of two other pentadecapeptides with the sameaminoacid composition but randomly scrambled primary sequences, using molecular dynamicsimulations. Our data demonstrates that whilst the peptides with scrambled sequences show nodefinite prevalent structure in solution, INGAP-PP maintains a notably stable tertiary fold, namely, aconformer with a central b-sheet and closed C-terminal. Such structure resembles the one correspondingto 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 scrambledsequences tested showed no biological activity, while INGAP-PP significantly increases b-cells functionand mass both in vitro and in vivo conditions. The capability of INGAP-PP to temporarily adopt otherclosely related conformations offers also a plausible explanation for the 50 fold experimental differencein potency between the active pentadecapepide and the whole protein. They also suggest that the Cterminalregion 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-PPanalogs, suitable for the prevention and treatment of diabetes.