Research Projects

Pancreastatin (PST) is a 52-amino acid peptide (human amino acid sequence: GESRSEALAVDGAGKPGAEEAQDPEGKGEQEHSQQKEEEEEMAVVPQGLFRG-amide) that is generated by proteolytic cleavage of chromogranin A, the major soluble protein in the neurotransmitter storage vesicles of neuroendocrine cells including pancreatic beta cells and adrenal medullary chromaffin cells. The active part of the PST peptide is located within its carboxyl-terminus 29 residues. Recent studies by us identified a common genetic variant (occurring in approximately 15% of Indian populations) within the active part of PST peptide which results in the change of amino acid glycine to serine; this variation corresponds to the 297th amino acid position of chromogranin A. Importantly, this genetic variation (Gly297Ser) displays strong associations with cardiometabolic diseases like diabetes, coronary artery disease and hypertension. Computational and binding studies show markedly higher interactions of the Gly297Ser variant peptide with the insulin receptor which forms the basis for its differential actions. The current study seeks to determine the structural and mechanistic bases of the differential impact of the Gly297Ser variant PST peptide (as compared to the wild-type PST peptide) that underlie the disease pathogenesis. In this direction, we will first determine the hitherto-unknown structures of the wild-type and variant PST peptides by means of nuclear magnetic resonance (NMR) techniques. Following this, the exact nature of the interactions of these peptides with the insulin receptor would be investigated by surface plasmon resonance (SPR). The peptides will also be characterized in vitro to gain mechanistic insights into pathophysiological conditions. In view of the potential regulatory role of the PST peptides in insulin signaling, the differential effects of the wild-type and Gly297Ser variant peptides on insulin signaling would be studied by assessment of changes in activation and/or gene expression of key effectors and downstream targets. Additionally, we plan to study the effect of the wild-type and Gly297Ser variant PST peptides on ROS generation and concomitant cellular processes since the pro-inflammatory roles of these peptides are likely to contribute to cardiometabolic disease risk. This study is anticipated to elucidate the structures of the physiological dysglycemic peptide pancreastatin for the first time and establish the molecular basis for enhanced cardiometabolic disease risk associated with pancreastatin Gly297Ser variant peptide.