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A Large-Scale Conformational Change Couples Membrane Recruitment to Cargo Binding in the AP2 Clathrin Adaptor Complex

DOI: 10.1016/j.cell.2010.05.006 DOI Help

Authors: Lauren Jackson (University of Cambridge) , Bernie Kelly (University of Cambridge) , Airlie Mccoy (University of Cambridge) , Thomas Gaffry (Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52 50931 Cologne, Germany) , Leo James (Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK) , Brett Collins (Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia) , Stefan Höning (2Institute of Biochemistry I and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52 50931 Cologne, Germany) , Philip Evans (3Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK) , David Owen (Cambridge Institute for Medical Research, Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell

State: Published (Approved)
Published: June 2010
Diamond Proposal Number(s): 261

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.

Journal Keywords: Cellbio; Proteins

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

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