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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography	A Large-Scale Conformational Change Couples Membrane Recruitment to Cargo Binding in the AP2 Clathrin Adaptor Complex Lauren Jackson , Bernie Kelly , Airlie Mccoy , Thomas Gaffry , Leo James , Brett Collins , Stefan Höning , Philip Evans , David Owen Cell DOI: 10.1016/j.cell.2010.05.006 Diamond Proposal Number(s): [261] Show Abstract ▼ Abstract: The AP2 adaptor complex (?, ?2, ?2, and ?2 subunits) crosslinks the endocytic clathrin scaffold to PtdIns4,5P2-containing membranes and transmembrane protein cargo. In the “locked” cytosolic form, AP2's binding sites for the two endocytic motifs, Yxx? on the C-terminal domain of ?2 (C-?2) and [ED]xxxL[LI] on ?2, are blocked by parts of ?2. Using protein crystallography, we show that AP2 undergoes a large conformational change in which C-?2 relocates to an orthogonal face of the complex, simultaneously unblocking both cargo-binding sites; the previously unstructured ?2 linker becomes helical and binds back onto the complex. This structural rearrangement results in AP2's four PtdIns4,5P2- and two endocytic motif-binding sites becoming coplanar, facilitating their simultaneous interaction with PtdIns4,5P2/cargo-containing membranes. Using a range of biophysical techniques, we show that the endocytic cargo binding of AP2 is driven by its interaction with PtdIns4,5P2-containing membranes.	Jun 2010
I03-Macromolecular Crystallography	A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex Bernie Kelly , Airlie Mccoy , Kira Spate , Sharon Miller , Stefan Honing , David Owen , Phil Evans Nature DOI: 10.1038/nature07422 PMID: 19140243 Show Abstract ▼ Abstract: Most transmembrane proteins are selected as transport-vesicle cargo through the recognition of short, linear amino-acid motifs in their cytoplasmic portions by vesicle coat proteins. For clathrin-coated vesicles, the motifs are recognized by clathrin adaptors. The AP2 adaptor complex (subunits ?, ?2, ?2 and ?2) recognizes both major endocytic motifs: Yxx? motifs1 (where ? can be F, I, L, M or V) and [ED]xxxL[LI] acidic dileucine motifs. Here we describe the binding of AP2 to the endocytic dileucine motif from CD4 (ref. 2). The major recognition events are the two leucine residues binding in hydrophobic pockets on ?2. The hydrophilic residue four residues upstream from the first leucine sits on a positively charged patch made from residues on the ?2 and ? subunits. Mutations in key residues inhibit the binding of AP2 to ‘acidic dileucine’ motifs displayed in liposomes containing phosphatidylinositol-4,5-bisphosphate, but do not affect binding to Yxx? motifs through ?2. In the ‘inactive’ AP2 core structure3 both motif-binding sites are blocked by different parts of the ?2 subunit. To allow a dileucine motif to bind, the ?2 amino terminus is displaced and becomes disordered; however, in this structure the Yxx?-binding site on ?2 remains blocked.	Nov 2008
I03-Macromolecular Crystallography	Decoding of Methylated Histone H3 Tail by the Pygo-BCL9 Wnt Signaling Complex Marc Fiedler , María José Sánchez-barrena , Maxim Nekrasov , Juliusz Mieszczanek , Vladimir Rybin , Jürg Müller , Phil Evans , Mariann Bienz Molecular Cell 30 (4), 507 - 518 DOI: 10.1016/j.molcel.2008.03.011 PMID: 18498752 Open Access Show Abstract ▼ Abstract: Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of β-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.	May 2008

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