Identification of candidate nsSNPs of the human FNDC5 gene and their structural and functional consequences using in silico analysis

Fibronectin type-III domain containing protein-5 (FNDC5), predominantly expressed in skeletal muscles, encodes FNDC5 transmembrane-protein. A segment of this protein is cleaved and secreted into blood as irisin, which promotes browning of white adipose tissue, leading to energy expenditure. It functions synergistically with fibroblast growth factor-21 (FGF21). Irisin is considered as a potential target for treating obesity-related disorders. Likewise, FNDC5 variations can contribute to development of such disorders. This study aimed to identify putative non-synonymous single nucleotide polymorphisms (nsSNPs) of human FNDC5, potentially impacting FNDC5-FGF21 interaction. Sequence and structure based computational tools were used to identify nsSNPs of FNDC5, which revealed eight nsSNPs as being most deleterious (N39K, R78H, R209H, T124I, L150P, L156V, V83M, and T86I). Molecular-docking was performed to analyze the impact of FNDC5 mutations on wild-type and mutant FNDC5-FGF21 complexes, revealing that T124I (rs185141197) and L150P (rs377741902) showed higher buried surface area (BSA) than wild-type. Following this, molecular dynamic (MD) simulation further affirmed the findings and revealed that T124I induced conformational changes in the irisin domain of FNDC5, which may significantly affect its binding with protein FGF21, potentially impairing synergistic effects of FNDC5 and FGF21 on adipocyte browning and increasing risk for developing obesity and related disorders.