Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.
Publication Type:Journal Article
Source:Cell, Volume 141, Issue 7, p.1183-94 (2010)
Keywords:Amino Acid Sequence, Cell Line, Crystallography, X-Ray, Cyclophilins, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Histones, Humans, Methylation, Models, Molecular, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Nuclear Magnetic Resonance, Biomolecular, Proline, Protein Interaction Domains and Motifs
<p>The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of histone H3K4me3/2 marks and recruitment of the cyclophilin CyP33. CyP33 contains a PPIase and a RRM domain and regulates MLL1 function through HDAC recruitment. We find that the PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. H3K4me3/2 and CyP33-RRM target different surfaces of MLL1-PHD3 and can bind simultaneously to form a ternary complex. Furthermore, the MLL1-CyP33 interaction is required for repression of HOXA9 and HOXC8 genes in vivo. Our results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment.</p>