Mol Cell Proteomics 2026 Mar 29;253:101518. doi: 10.1016/j.mcpro.2026.101518.

Histone Variant H2A.Z Enhances Histone and Nucleosome Dynamics.

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Interchanging canonical histone H2A with variant H2A.Z in chromatin complexes is vital for the proper regulation of transcription, DNA damage repair, and centromere maintenance. However, the physical mechanisms underlying functional differences between H2A and H2A.Z complexes are unclear. Human H2A and H2A.Z exhibit high sequence and structural conservation, with subtle differences in the H2A DNA-binding loops. In this study, we employ hydrogen-deuterium exchange coupled with mass spectrometry and molecular dynamics simulation to investigate the differences in solution behavior between human H2A-H2B and H2A.Z-H2B. We demonstrate that replacing H2A with H2A.Z enhances the dynamics of the refolded histone heterodimer, whether it is in nucleosomes, in complex with H3-H4, or alone in solution. In all situations, enhanced dynamics are observed for H2B, suggesting altered interaction with H2A.Z and DNA. Parallel comparisons of H2A-H2B orthologs between humans and frogs reveal fewer differences in dynamics. Our findings provide mechanistic insights into the function of histone variants and reveal how differences in dynamics may underlie functional differences between structurally similar proteins.

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