The role of histone H3 leucine 126 in fine-tuning the copper reductase activity of nucleosomes

The copper reductase activity of histone H3 suggests undiscovered characteristics within the protein. Here, we investigated the function of leucine 126 (H3L126), which occupies an axial position relative to copper binding. Typically found as a methionine or leucine in copper binding proteins, the axial ligand influences the reduction potential of the bound ion, modulating its tendency to accept or yield electrons. We found that mutation of H3L126 to methionine (H3L126M) enhanced the enzymatic activity of native yeast nucleosomes in vitro and increased intracellular levels of Cu1+, leading to improved copper-dependent activities including mitochondrial respiration and growth in oxidative media with low copper. Conversely, H3L126 to histidine (H3L126H) mutation decreased nucleosome’s enzymatic activity and adversely affected copper-dependent activities in vivo. Our findings demonstrate that H3L126 fine-tunes the copper reductase activity of nucleosomes and highlight the utility of nucleosome enzymatic activity as a novel paradigm to uncover previously unnoticed features of histones.