Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression.
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.
Wang
Zhanxin
Z
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Song
Jikui
J
Milne
Thomas A
TA
Wang
Gang G
GG
Li
Haitao
H
Allis
C David
CD
Patel
Dinshaw J
DJ
D000595:Amino Acid Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D021983:Cyclophilins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011392:Proline / Q000737:chemistry; D054730:Protein Interaction Domains and Motifs
D006657:Histones; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011392:Proline; D011495:Histone-Lysine N-Methyltransferase; D006655:Histone Deacetylases; D021983:Cyclophilins; C114522:PPIE protein, human