Abstract
Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism's genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.
Highlights
Peroxisome proliferator-activated receptor-G coactivator 1-alpha (PPARGC1A, PGC-1α, or PGC-1) is a transcriptional coactivator of peroxisome proliferator-activated receptor gamma (PPAR-γ), which regulates the energy metabolism’s genes and mitochondrial biogenesis [1, 2]
We investigated the effect of Gly482Ser polymorphism on nonalcoholic fatty liver disease (NAFLD) and the risk of coronary artery disease (CAD) among patients with type 2 diabetes mellitus (T2DM) [26,27,28]
We focused on investigating that the changes in the dynamic behavior of PPARGC1A was induced by the pathogenic G>A Gly482Ser variant
Summary
Peroxisome proliferator-activated receptor-G coactivator 1-alpha (PPARGC1A, PGC-1α, or PGC-1) is a transcriptional coactivator of peroxisome proliferator-activated receptor gamma (PPAR-γ), which regulates the energy metabolism’s genes and mitochondrial biogenesis [1, 2]. The nuclear receptor PPAR-γ enables PPARGC1A to interact with various transcription factors. PGC-1α regulates the cAMP (cyclic adenosine monophosphate) response elementbinding protein (CREB) and nuclear respiratory factors (NRFs). The PGC-1α protein is associated with controlling blood pressure, cellular cholesterol homeostasis, and obesity [3, 4]. The PGC-1α encoding gene plays an essential role in cardiovascular and metabolic diseases. It regulates the pathophysiological processes contributing to coronary artery disease (CAD) [5,6,7]
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