Islet neogenesis associated protein (ingap): structural and dynamical properties of its active pentadecapeptide.
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 amino acid 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 beta-sheet and closed C-terminal. Such structure resembles the one corresponding to the amino acid 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 beta-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 pentadecapeptide 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.
McCarthy
Andrés N
AN
Instituto de Física de Líquidos y Sistemas Biológicos, (CONICET La Plata-UNLP-CIC) 59N(o) 789, c.c. 565, B1900BTE La Plata, Buenos Aires, Argentina. amccarthy@iflysib.unlp.edu.ar
Mogilner
Inés G
IG
Grigera
J Raúl
JR
Borelli
M Inés
MI
Del Zotto
Hector
H
Gagliardino
Juan José
JJ
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; C000612141:REG3A protein, human