Three Novel Mutations I65S, R66S, and G86R Divulge Significant Conformational Variations in the PTB Domain of the IRS1 Gene

Abstract

Insulin receptor substrate 1 (IRS1) is one of the major substrates for the IR, and their interaction mediates several downstream insulin signaling pathways. In this study, we have identified three novel mutations in the IRS1 gene of type 2 diabetic (T2D) patients, which reflected in the amino acid changes as I65S, R66S, and G86R in the phosphotyrosine binding domain of the IRS1 protein. The impact of these mutations on the structure and function of the IRS1 protein was evaluated through molecular modeling studies, and distinct conformational fluctuations were recorded. The variable binding affinities and positional displacement of these mutant models were observed in the ligand-binding cleft of IR. The mutant IRS1 models triggered conformational changes in the L1 domain of IR upon their binding. Such structural variations in IRS1 and IR structures due to mutations resulted in variable molecular interactions that could lead to altered insulin transduction, followed by insulin resistance and T2D.