title: Evolutionary adaptation of the fly Pygo PHD finger toward recognizing histone H3 tail methylated at arginine 2.
abstract: Pygo proteins promote Armadillo- and β-catenin-dependent transcription, by relieving Groucho-dependent repression of Wnt targets. Their PHD fingers bind histone H3 tail methylated at lysine 4, and to the HD1 domain of their Legless/BCL9 cofactors, linking Pygo to Armadillo/β-catenin. Intriguingly, fly Pygo orthologs exhibit a tryptophan > phenylalanine substitution in their histone pocket-divider which reduces their affinity for histones. Here, we use X-ray crystallography and NMR, to discover a conspicuous groove bordering this phenylalanine in the Drosophila PHD-HD1 complex--a semi-aromatic cage recognizing asymmetrically methylated arginine 2 (R2me2a), a chromatin mark of silenced genes. Our structural model of the ternary complex reveals a distinct mode of dimethylarginine recognition, involving a polar interaction between R2me2a and its groove, the structural integrity of which is crucial for normal tissue patterning. Notably, humanized fly Pygo derepresses Notch targets, implying an inherent Notch-related function of classical Pygo orthologs, disabled in fly Pygo, which thus appears dedicated to Wnt signaling.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Thomas C R
authors.initials: TC
authors.lastname: Miller
authors.forename: Juliusz
authors.initials: J
authors.lastname: Mieszczanek
authors.forename: María José
authors.initials: MJ
authors.lastname: Sánchez-Barrena
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Marc
authors.initials: M
authors.lastname: Fiedler
authors.forename: Mariann
authors.initials: M
authors.lastname: Bienz
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D051880:Receptors, Notch / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D051153:Wnt Proteins; C487735:dimethylarginine; C453400:pygo protein, Drosophila; D001120:Arginine