Structural and conformational changes induced by missense variants in the zinc finger domains of GATA3 involved in breast cancer

Abstract

Breast cancer (BC) is the main cancer in women having multiple receptor based tumour subtypes. Large scale genome sequencing studies of BC have identified several genes among which GATA3 is reported as a highly mutated gene followed by TP53 and PIK3CA. GATA3 is a crucial transcription factor, and was initially identified as a DNA-binding protein involved in the regulation of immune cell functions. Different missense mutations in the region of the DNA-binding domain of GATA3 are associated with BC and other neoplastic disorders. In this study, computational based approaches have been exploited to reveal associations of various mutations on structure, stability, conformation and function of GATA3. Our findings have suggested that, all analysed missense mutations were deleterious and highly pathogenic in nature. A molecular dynamics simulation study showed that all mutations led to structural destabilisation by reducing protein globularity and flexibility, by altering secondary structural configuration and decreasing protein ligand stability. Essential dynamics analysis indicated that mutations in GATA3 decreased protein mobility and increased its conformational instability. Furthermore, residue network analysis showed that the mutations affected the signal transduction of important residues that potentially influenced GATA3-DNA binding. The present study highlights the importance of different variants of GATA3 which have potential impact on neoplastic progression in breast cancer and may facilitate development of precise and personalized therapeutics.