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Mol. Cell. Biol. doi:10.1128/MCB.00849-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Syntenin-1 is a new component of tetraspanin-enriched microdomains: mechanisms and consequences of the interaction of syntenin-1 with CD63

Cancer Research UK Institute for Cancer Studies and School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, UK

^* To whom correspondence should be addressed. Email: f.berditchevski{at}bham.ac.uk.

	Abstract

Tetraspanins are clustered in specific microdomains (named tetraspanin-enriched microdomains, or TERM) in the plasma membrane and regulate the functions of associated transmembrane receptors including integrins and receptor tyrosine kinases. We have identified syntenin-1, a PDZ domain - containing protein, as a new component of TERM and show that syntenin-1 specifically interacts with the tetraspanin CD63. Detailed biochemical and heteronuclear magnetic resonance spectroscopy (NMR) studies have demonstrated that the interaction is mediated by the C-terminal cytoplasmic region of the tetraspanin and the PDZ domains of syntenin-1. Upon interaction, NMR chemical shift perturbations were predominantly localised to residues around the binding pocket of PDZ1, indicating a specific mode of recognition of the cytoplasmic tail of CD63. In addition, the C-terminus of syntenin-1 has a stabilising role in the CD63-syntenin-1 association as deletion of the last 17 amino acids abolished the interaction. The CD63-syntenin-1 complex is abundant on the plasma membrane and the elevated expression of the wild-type syntenin-1 slows down constitutive internalisation of the tetraspanin. Furthermore, internalisation of CD63 was completely blocked in cells expressing a syntenin-1 mutant lacking the first 100 amino acids. Previous results have shown that CD63 is internalised via AP-2 - dependent mechanisms. Hence, our data indicate that syntenin-1 can counteract the AP-2 - dependent internalisation, and identify this tandem PDZ protein as a new regulator of endocytosis.

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