Abstract
SummaryPygo 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.
Highlights
Wnt/b-catenin signaling controls numerous steps in the normal development and tissue homeostasis of animals (Cadigan and Nusse, 1997; Clevers, 2006)
Pygo proteins promote Armadillo- and b-catenindependent transcription, by relieving Grouchodependent repression of Wnt targets. Their PHD fingers bind histone H3 tail methylated at lysine 4, and to the homology domain 1 (HD1) domain of their Legless/BCL9 cofactors, linking Pygo to Armadillo/b-catenin
Fly Pygo orthologs exhibit a tryptophan > phenylalanine substitution in their histone pocket-divider which reduces their affinity for histones
Summary
Wnt/b-catenin signaling controls numerous steps in the normal development and tissue homeostasis of animals (Cadigan and Nusse, 1997; Clevers, 2006). Hyperactivation of this pathway leads to many types of cancer, most notably colorectal cancer (Bienz and Clevers, 2000). The transcriptional activity of Armadillo during Drosophila development depends on a highly conserved nuclear protein complex, consisting of Pygo (Pygo) and Legless (Lgs) (Belenkaya et al, 2002; Kramps et al, 2002; Parker et al, 2002; Thompson et al, 2002). Rescue assays demonstrated that both interactions are essential for Drosophila development (Hoffmans and Basler, 2004; Townsley et al, 2004a)
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