Structural Evaluation and Conformational Dynamics of ZNF141T474I Mutation Provoking Postaxial Polydactyly Type A

Abstract

Postaxial Polydactyly (PAP) is a congenital disorder of limb abnormalities characterized by posterior extra digits. Mutations in the N-terminal region of the Zinc finger protein 141 (ZNF141) gene were recently linked with PAP type A. Zinc finger proteins exhibit similarity at their N-terminal regions due to C2-H2 type Zinc finger domains, but their functional preferences vary significantly by the binding patterns of DNA. Methods: This study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.1420C > T; p.T474I) in ZNF141 gene segregating PAP through a molecular dynamics simulations approach. Results: In ZNF141 protein, helices play a crucial role by attaching three specific target DNA base pairs. In ZNF141T474I protein, H1, H3, and H6 helices attain more flexibility by acquiring loop conformation. The outward disposition of the proximal portion of H9-helix in mutant protein occurs due to the loss of prior beta-hairpins at the C terminal region of the C2-H2 domain. The loss of hydrogen bonds and exposure of hydrophobic residues to solvent and helices turning to loops cause dysfunction of ZNF141 protein. These significant changes in the stability and conformation of the mutant protein were validated using essential dynamics and cross-correlation maps, which revealed that upon point mutation, the overall motion of the proteins and the correlation between them were completely different, resulting in Postaxial polydactyly type A. Conclusions: This study provides molecular insights into the structural association of ZNF141 protein with PAP type A. Identification of active site residues and legends offers new therapeutic targets for ZNF141 protein. Further, it reiterates the functional importance of the last residue of a protein.