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Naturally Occurring Variants of the Dysglycemic Peptide Pancreastatin DIFFERENTIAL POTENCIES FOR MULTIPLE CELLULAR FUNCTIONS AND STRUCTURE-FUNCTION CORRELATION

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Title Naturally Occurring Variants of the Dysglycemic Peptide Pancreastatin DIFFERENTIAL POTENCIES FOR MULTIPLE CELLULAR FUNCTIONS AND STRUCTURE-FUNCTION CORRELATION
 
Creator ALLU, PKR
CHIRASANI, VR
GHOSH, D
MANI, A
BERA, AK
MAJI, SK
SENAPATI, S
MULLASARI, AS
MAHAPATRA, NR
 
Subject Genetic Polymorphism
Glucose Metabolism
Metabolic Diseases
Molecular Modeling
Nitric Oxide
Peptide Hormones
Glucose Uptake
Human Genetic Variation
Metabolic Disorder
Pancreastatin
A-DERIVED PEPTIDE
DEPENDENT DIABETES-MELLITUS
NITRIC-OXIDE SYNTHESIS
CHROMOGRANIN-A
RAT ADIPOCYTES
GLUCOSE-UPTAKE
L-ARGININE
DISEASE
MECHANISMS
CATESTATIN
 
Description 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 Ca2+ levels in various cell types. In addition, PST peptides activated gluconeogenic genes in the following order: PST-297S approximate to PST-287K > PST-WT. Consistent with these in vitro results, the common PST variant allele Ser-297 was associated with significantly higher (by approximate to 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 -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 -helix was: PST-297S approximate to PST-287K > PST-WT). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in approximate to 300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis.
 
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
 
Date 2014-12-28T10:51:19Z
2014-12-28T10:51:19Z
2014
 
Type Article
 
Identifier JOURNAL OF BIOLOGICAL CHEMISTRY, 289(7)4455-4469
0021-9258
1083-351X
http://dx.doi.org/10.1074/jbc.M113.520916
http://dspace.library.iitb.ac.in/jspui/handle/100/16285
 
Language English