We report two NMR complex structures of PHDUHRF1 binding to unmodified or K9 trimethylated histone tails, which clarify a controversy regarding how the binding of UHRF1 to H3 tails is mediated. Based on our structures, H3R2, not H3K9, mediates PHD binding.

To address this issue, we determined 3D NMR structures of free PHDUHRF1, and two complexes, namely PHDUHRF1-H3K9me0 and PHDUHRF1-H3K9me3 (Figure 1 and Supplementary information, Data S1, Figure S1, Table S2). In these three structures, PHDUHRF1 is coordinated by three zinc ions to form a rod-shape structure, containing a small α-helix, a double-stranded anti-parallel β-sheet and three loops. The free and bound PHDUHRF1 structures have backbone atoms RMSD value of 1.7 Å, indicating that H3 peptides binding does not induce overall major conformational changes of PHDUHRF1. The C-terminus of PHDUHRF1 is coordinated by two zinc ions in an interleaved, compact manner, which is similar to the reported histone tail-binding PHD domain structures (Figure 1) 6, 7, 8, 9, 10, 11, 12, 13. However, a difference lies at the N-terminus of the PHDUHRF1, where the first zinc ion coordinates the N-terminal loop region. Such a structural feature is not found in other histone-binding PHD domains 6, 7, 8, 9, 10, 11, 12, 13, although the function of this loop remains unknown.

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