One of the long-standing questions in the field of chromatin biology is how histone-modifying enzymes are tethered to a specific promoter region. Dr. Couture laboratory at OISB and BMI has recently found that Ash2L, a protein interacting with the histone H3 lysine 4 methyltransferase MLL1, harbors a novel helix-wing-helix DNA binding domain that is needed for targeting and H3K4 trimethylation in vivo. Given that MLL1 is linked to acute forms of leukemia, these findings will eventually guide structure-based drug discoveries for the treatment of leukemia and other MLL-linked disorders. Their work is published in Nature Structural and Molecular Biology (Sarvan, et al. 2011 http://www.nature.com/nsmb/journal/v18/n7/full/nsmb.2093.html)
(a) Overall structure of ASH2L N-terminal domain. β-strands and α-helices are rendered in blue and orange, respectively; the zinc atom is depicted in green. (b) ASH2L harbors a structurally conserved helix-wing-helix domain. Evolutionarily conserved surface residues are colored according to the sequence alignment (Supplementary Fig. 1). (c) Superimposition of ASH2L and FOXO4 HWH domains. ASH2L is rendered as in a, and FOXO4 is colored in gray. (d,e) Electrostatic potential surface of FOXO4 (d) and ASH2L (e). DNA carbon atoms are rendered in yellow. Electrostatic potentials are contoured from +10 kBTe−1 (blue) to −10 kBTe−1 (red), where e is the electron, T is temperature and kB is the Boltzmann constant. Arrows indicate the canonical and putative DNA binding α-helix of FOXO4 and ASH2L.