Histone Peptide Recognition by KDM5B-PHD1: A Case Study.

A detailed understanding of the energetic contributions to histone peptide recognition would be valuable for a better understanding of chromatin anchoring mechanisms and histone diagnostic design. Here, we probed the energetic contributions to recognize the same unmodified histone H3 by three different plant homeodomain (PHD) H3K4me0 readers: hKDM5B-PHD1 (first PHD finger of hKDM5B), hBAZ2A-PHD, and hAIRE-PHD1. The energetic contributions of residues differ significantly from one complex to the next. For example, H3K4A substitution completely aborts the formation of the hAIRE-histone peptide complex, while it has only a small destabilizing effect on binding of the other readers, even though H3K4 methylation disrupts all three complexes. Packing density suggests that methylation of more tightly packed Lys/Arg residues can disrupt binding, even if the energetic contribution is small. The binding behavior of hKDM5B-PHD1 and hBAZ2A-PHD is similar, and like PHD H3R2 readers, both possess a pair of Asp residues in the treble clef for interaction with H3R2. PHD subtype sequences, especially the tandem PHD-PHD fingers, show enrichment in the treble clef Asp residues, suggesting that it is a subtype-specific property. These Asp residues make significant energetic contributions to the formation of the hKDM5B-histone peptide complex, suggesting that there are interactions in addition to those reported in the recent NMR structure. However, the presence of the treble clef Asp in PHD sequences may not always be sufficient for histone peptide binding. This study showcases reader-histone peptide interactions in the context of residue conservation, energetic contributions, interfacial packing, and sequence-based reader subtype predictability.