Analyzing Binding Sites of EXT1, EXT2, PTPN11 and FUT7 in the Context of Multiple Hereditary Exostoses Pathogenesis Using AlphaFold

Abstract

Multiple hereditary exostoses (MHE) is a genetic disorder characterized by the formation of benign osteochondromas. Pathogenic variants in the EXT1 and EXT2 genes represent the molecular cause of MHE, although there are cases with unknown etiology. Recent studies suggest that proteins such as FUT7 and PTPN11 could also be involved in the pathogenesis of MHE. In this study, using AlphaFold modeling, we analyzed protein interactions between EXT1, EXT2, their pathogenic variants, FUT7, and PTPN11. We confirmed a robust interaction between EXT1 and EXT2, essential for the formation of the native glycosyltransferase complex; disruption of this interaction might explain pathogenicity of previously described variants. No direct binding sites were detected between EXT1 and FUT7. However, our study revealed potential consensus binding sites between EXT1 and PTPN11, indicating its possible involvement in MHE pathogenesis. Our findings provide insights into the molecular basis of MHE, suggesting further avenues for research and potential therapeutic approaches.