Overcharging of the Zinc Ion in the Structure of the Zinc-Finger Protein Is Needed for DNA Binding Stability

Abstract

Zinc-finger structure, in which a Zn2+ ion binds to four cysteines or histidines in a tetrahedral structure, is a very common motif of nucleic acid-binding proteins. The corresponding interaction model is present in 3% of the genes in the human genome. As a result, the zinc finger has been extremely useful in various therapeutic and research capacities and in biotechnology. In a stable configuration of the zinc finger, the cysteine amino acids are deprotonated and become negatively charged. Thus, the Zn2+ ion is overscreened by four cysteine charges (overcharged). Whether this overcharged configuration is also stable when such a negatively charged zinc finger binds to a negatively charged DNA molecule is unknown. We investigated how the deprotonated state of cysteine influences its structure, dynamics, and function in binding to DNA molecules by using an all-atom molecular dynamics simulation up to the microsecond range of an androgen receptor protein dimer. Our results showed that the deprotonated state of cysteine residues is essential for the mechanical stabilization of the functional, folded conformation. This state stabilizes not only the protein structure but also the protein–DNA binding complex. The differences in the structural and energetic properties of the two sequence-identical monomers are also investigated and show the strong influence of DNA on the structure of the zinc-finger protein dimer upon complexation. Our result can potentially lead to a better molecular understanding of one of the most common classes of zinc fingers.

Crotalaria verrucosa Leaf Extract Mediated Synthesis of Zinc Oxide Nanoparticles: Assessment of Antimicrobial and Anticancer Activity

“…Zinc is considered to be a significant trace element in tissues of the body, such as brain, muscle, bone, and skin, maintaining many physiological functions and without which few enzymes namely carbonic anhydrase, carboxypeptidase, and alcohol dehydrogenase become quiescent [4]. Being a central component of different enzymes, zinc is involved in body metabolism and plays a vital role in hematopoiesis, synthesis of proteins and nucleic acid [5][6][7]. While, the eukaryotes are found resistant to lower concentrations of zinc oxide NPs [8].…”

FREEDA: an automated computational pipeline guides experimental testing of protein innovation by detecting positive selection

“…4) to experimentally solved structures of their orthologues in complex with binding partners (see Methods for details). Two intrinsically disordered CXXC motifs within the Yippee domain of MIS18β together form a tetrahedral module whose four conserved cysteins bind a zinc ion (Subramanian et al, 2016), likely stabilizing protein conformation (Nguyen et al, 2020). Aligning mouse MIS18β to the crystal structure of the fission yeast MIS18 Yippee-like domain ((Subramanian et al, 2016); Fig.…”

Nitric Oxide Mobilizes Intracellular Zn2+ via the GC/cGMP/PKG Signaling Pathway and Stimulates Adipocyte Differentiation

“…Furthermore, several zinc finger proteins were reported to regulate adipocyte differentiation [ 33 ]. Nguyen’s study demonstrated that overcharging of Zn 2+ in the structure of the zinc finger protein Is needed for DNA binding stability [ 34 ]. Therefore, intracellular Zn 2+ deficiency may affect the structure of the zinc finger protein and lead to DNA binding instability.…”