Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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Binding Sites
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Crystallography, X-Ray
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Drosophila Proteins / chemistry
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster
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Histones / chemistry
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Histones / genetics
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Histones / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lysine / metabolism
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Methylation
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Models, Molecular
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Molecular Sequence Data
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Peptides / chemistry
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Peptides / genetics
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Peptides / metabolism
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Protein Binding
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Protein Conformation
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sequence Alignment
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Signal Transduction / physiology*
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Transcription Factors
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Wnt Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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BCL9 protein, human
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Drosophila Proteins
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Histones
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Intracellular Signaling Peptides and Proteins
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Lgs protein, Drosophila
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Multiprotein Complexes
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Neoplasm Proteins
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PYGO1 protein, human
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Peptides
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Recombinant Fusion Proteins
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Transcription Factors
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Wnt Proteins
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pygo protein, Drosophila
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Lysine