posted on 2021-12-03, 20:51authored byPrasanna K. R. Allu, Malapaka Kiranmayi, Sromona D. Mukherjee, Venkat R. Chirasani, Richa Garg, Durairajpandian Vishnuprabu, Sudesh Ravi, Lakshmi Subramanian, Bhavani S. Sahu, Dhanya R. Iyer, Sakthisree Maghajoti, Saurabh Sharma, Marimuthu S. Ravi, Madhu Khullar, Arasambattu K. Munirajan, Jiaur R. Gayen, Sanjib Senapati, Ajit S. Mullasari, Viswanathan Mohan, Venkatesan Radha, Sathyamangala V. Naga Prasad, Nitish R. Mahapatra
Pancreastatin (PST), a chromogranin A (CHGA)-derived
potent physiological dysglycemic peptide, regulates glucose/insulin
homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser;
rs9658664) that occurs in a large section of human populations. Association
analysis of this single nucleotide polymorphism with cardiovascular/metabolic
diseases states in Indian populations (n≈4300 subjects) displays elevated
plasma glucose, glycosylated hemoglobin, diastolic blood pressure and
catecholamines in Gly/Ser subjects as compared to wild-type individuals
(Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3-1.6-fold)
for type-2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In
corroboration, the variant peptide (PST-297S) displays gain-of-potency in
several cellular events relevant for cardiometabolic disorders (e.g., increased expression of
gluconeogenic genes, increased catecholamine secretion, greater inhibition of
insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT).
Computational docking analysis and molecular dynamics simulations show higher
affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78)
and insulin receptor (IR) than PST-WT, providing a mechanistic basis for the
enhanced activity of the variant peptide. In
vitro binding assays validate these in
silico predictions of PST peptides binding to GRP78 and IR. In conclusion,
the PST 297Ser allele influences cardiovascular/metabolic phenotypes and
emerges as a novel risk factor for type-2 diabetes/hypertension/coronary artery
disease in human populations.
Funding
This work was supported by a grant (SR/SO/HS-084/2013A) from the SERB, DST, Govt. of India to NRM, VR and VM. This work was also supported by a grant (SPARC/2018-2019/P652/SL) from the MHRD, Govt. of India to NRM and SVNP. This work was also supported in part by a grant (BT/PR4820/MED/12/622/2013) from the DBT, Govt. of India to AKM.