GAS41 recognizes di-acetylated histone H3 through a bivalent binding mode.

GAS41 is a chromatin-associated protein that belongs to the YEATS family and is involved in the recognition of acetyl-lysine in histone proteins. A unique feature of GAS41 is the presence of a C-terminal coiled-coil domain, which is responsible for protein dimerization. Here, we characterized specificity of the GAS41 YEATS domain, and found that it preferentially binds to acetylated H3K18 and H3K27 peptides. Interestingly, we found that full-length, dimeric GAS41 binds to di-acetylated H3 peptides with an enhanced affinity when compared to mono-acetylated peptides, through a bivalent binding mode. We determined the crystal structure of the GAS41 YEATS domain with H3K23acK27ac to visualize the molecular basis of di-acetylated histone binding. Our results suggest a unique binding mode in which full-length GAS41 is a reader of di-acetylated histones.