Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.
Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of beta-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.
Fiedler
Marc
M
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Sánchez-Barrena
María José
MJ
Nekrasov
Maxim
M
Mieszczanek
Juliusz
J
Rybin
Vladimir
V
Müller
Jürg
J
Evans
Phil
P
Bienz
Mariann
M
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C111180:BCL9 protein, human; D029721:Drosophila Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C453403:Lgs protein, Drosophila; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C453402:PYGO1 protein, human; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C453400:pygo protein, Drosophila; D008239:Lysine