The chromodomain of HP1á binds directly to lysine 9-methylated histone H3 (H3K9me). This interaction is enhanced by phosphorylation of serine residues in the N-terminal tail of HP1á by unknown mechanism. Here we show that phosphorylation modulates flexibility of HP1á's N-terminal tail, which strengthens the interaction with H3. NMR analysis of HP1á's chromodomain with N-terminal tail reveals that phosphorylation does not change the overall tertiary structure, but apparently reduces the tail dynamics. Small angle X-ray scattering confirms that phosphorylation contributes to extending HP1á's N-terminal tail. Systematic analysis using deletion mutants and replica exchange molecular dynamics simulations indicate that the phosphorylated serines and following acidic segment behave like an extended string and dynamically bind to H3 basic residues; without phosphorylation, the most N-terminal basic segment of HP1á inhibits interaction of the acidic segment with H3. Thus, the dynamic string-like behavior of HP1á's N-terminal tail underlies the enhancement in H3 binding due to phosphorylation.
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