Breast cancer mutation in GATA3 zinc finger 1 induces conformational changes leading to the closer binding of ZnFn2 with a wrapping architecture.

GATA3 is a transcription factor, known to regulate the transcriptional network and several pathways using two zinc fingers. Its mutation is associated with a higher risk of breast cancer. The molecular mechanisms of these mutations are poorly understood. It recognizes -GATA- sites on the DNA, using its two zinc fingers ZnFn1 and ZnFn2. Mutations in ZnFn2 have been studied in the past and well known but recently ZnFn1 mutations are also being reported very frequently in breast cancer patients and there is very less knowledge available regarding the binding modes and mechanism. Here, we have investigated the structural and functional impact of GATA3 mutation M294K on the DNA-binding property. The structure was obtained and mutation was induced before subjecting it to the molecular docking followed by MD simulation. Our findings indicate that the somatic mutation M294K, reported in the GATA3 gene destabilizes the unbound structure but, when it forms the DNA-complex, its overall structural stability is restored by the wrapping architecture of ZnFn2 around the DNA in the palindromic region, leading to the enhanced kinetic stability. The mutation not only affects the ZnFn1 region alone but also influences the whole complex by inducing the conformational changes in the linker region between the two zinc fingers, bringing the two zinc fingers to closer proximity representing the flexibility in binding sites. Our findings provide a better understanding of ZnFn1 mutations and the possibility of a different strategy to target these genes for their clinical relevance.Communicated by Ramaswamy H. Sarma.