Human bromodomains: Structural determinants underlying site preferences

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Abstract
Bromodomains (BDs) are acetyllysine (Kac) interaction modules that bind to acetylated histone tails and other proteins. It is generally appreciated that BDs preferentially bind histone tail peptides that are multiply acetylated, but it is less well understood how individual sites, or combinations of sites, might be selected in this context. Here, we comprehensively profile human BD site preferences using histone H3 and H4 peptides with different numbers and combinations of acetylated lysines. Several general types of recognition emerge from this analysis, and residues from both the peptide and bromodomain appear to govern preferred binding combinations. To further explore this, we use alanine-scanning or homology-based mutagenesis of single residues or larger motifs, identifying a number of residues as important for binding. Notably, we also identify BD variants that change binding specificity or increase binding affinity for acetylated peptides. Our data identify subtle differences in binding patterns even among closely related bromodomains and reveal that multiple factors likely combine to enforce these preferences.

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