Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation.
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: E287K and G297S. 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 Ca(2+) 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 Ser-297 was associated with significantly higher (by ∼17 mg/dl, as compared with the wild-type Gly-297 allele) plasma glucose level in our study population (n = 410). Molecular modeling and molecular dynamics simulations predicted the following rank order of α-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 α-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.
['Allu|Prasanna K R|PK|', 'Chirasani|Venkat R|VR|', 'Ghosh|Dhiman|D|', 'Mani|Anitha|A|', 'Bera|Amal K|AK|', 'Maji|Samir K|SK|', 'Senapati|Sanjib|S|', 'Mullasari|Ajit S|AS|', 'Mahapatra|Nitish R|NR|']
D041721:3T3-L1 Cells D000328:Adult D019943:Amino Acid Substitution D000818:Animals D001786:Blood Glucose D002942:Circular Dichroism D005260:Female D014644:Genetic Variation D056945:Hep G2 Cells D006801:Humans D007328:Insulin D008297:Male D051379:Mice D020125:Mutation, Missense D010187:Pancreatic Hormones D017434:Protein Structure, Tertiary D013329:Structure-Activity Relationship
Pancreastatin Glucose Uptake Nitric Oxide Molecular Modeling Genetic Polymorphism Glucose Metabolism Human Genetic Variation Metabolic Diseases Metabolic Disorder Peptide Hormones