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First published online 28 June 2005
doi: 10.1242/jcs.02451

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Non-canonical YXXG endocytic motifs: recognition by AP2 and preferential utilization in P2X4 receptors

Stephen J. Royle^1,2, Omar S. Qureshi¹, Laura K. Bobanovi¹, Philip R. Evans², David J. Owen³ and Ruth D. Murrell-Lagnado^1,*

¹ Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
² MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK
³ Cambridge Institute for Medical Research, Department of Clinical Biochemistry, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK

^* Author for correspondence (e-mail: rdm1003{at}cam.ac.uk)

Accepted 21 April 2005

During clathrin-mediated endocytosis, proteins on the cell surface are selected for inclusion in clathrin-coated vesicles by clathrin adaptors, mainly the adaptor complex AP2. The P2X4 subtype of ATP-gated ion channel has in its C-terminus two putative endocytic motifs: a canonical YXX motif and a non-canonical YXXG motif (YEQGL). We demonstrate that endocytosis of P2X4 receptors is mediated preferentially by the YXXG motif because the YXX motif is inaccessible to AP2 owing to the structure of the channel. The crystal structure of a complex between residues 160-435 of the µ2 subunit of AP2 and a P2X4 C-terminal peptide showed that the YEQGL motif binds to µ2 at the same site as YXX motifs. Y and residues are accommodated in the same hydrophobic pockets in µ2 with the extra residue between them being accommodated by changes in the peptide's backbone configuration, when compared to YXX motifs. These data demonstrate that the family of potential tyrosine-based endocytic signals must be expanded to include motifs with an additional glycine at Y+3 (YXXG).

Key words: Endocytosis, Adaptors, Clathrin, P2X, Trafficking

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