Molecular basis for chromatin binding and regulation of MLL5

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 28; pp. 11296 - 11301
• Main Authors: Ali, Muzaffar, Rincón-Arano, Héctor, Zhao, Wei, Rothbart, Scott B., Tong, Qiong, Parkhurst, Susan M., Strahl, Brian D., Deng, Lih-Wen, Groudine, Mark, Kutateladze, Tatiana G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.07.2013; National Acad Sciences
• Subjects: Amino Acid Sequence; Antibodies; Biological Sciences; Cell cycle; Chromatin; Chromatin - metabolism; Crystal structure; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Drosophila; Genes; Histones; Homeostasis; Humans; Leukemia; Models, Molecular; Molecular Sequence Data; Phosphorylation; Promoter regions; Protein Binding; Protein Conformation; Protein isoforms; Proteins; Sequence Homology, Amino Acid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1310156110

The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His–Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin.