Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation [DNA and Chromosomes]

December 12th, 2013 by Allu, P. K. R., Chirasani, V. R., Ghosh, D., Mani, A., Bera, A. K., Maji, S. K., Senapati, S., Mullasari, A. S., Mahapatra, N. R.

Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST also triggers glycogenolysis in liver and reduces glucose uptake in adipocytes and hepatocytes. Here, we probed for genetic variations in PST sequence and identified two variants within its functionally important carboxyl-terminus domain: Glu287Lys and Gly297Ser. To understand functional implications of these amino-acid substitutions, we tested the effects of wild-type (PST-WT), PST-287K and PST-297S peptides on various cellular processes/events. The rank order of efficacy to inhibit insulin-stimulated glucose-uptake was: PST-297S>PST-287K>PST-WT. The PST peptides also displayed the same order of efficacy for enhancing intracellular nitric oxide and Ca2+ levels in various cell types. In addition, PST peptides activated gluconeogenic genes in the following order: PST-297S≥PST-287K>PST-WT. Consistent with these in vitro results, the common PST variant allele 297Ser was associated with significantly higher (by ~17 mg/dl, as compared to the wild-type Gly297 allele) plasma glucose level in our study population (n=410). Molecular modelling and molecular dynamics simulations predicted the following rank order of alpha-helical content: PST-297S>PST-287K>PST-WT. Corroboratively, circular dichroism analysis of PST peptides revealed significant differences in global structures (e.g., the order of propensity to form alpha-helix was: PST-297S≈PST-287K>PST-WT). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in ~300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis.
  • Posted in Journal of Biological Chemistry, Publications
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