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Molecular and Cellular Biology, October 2006, p. 7707-7718, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00849-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Syntenin-1 Is a New Component of Tetraspanin-Enriched Microdomains: Mechanisms and Consequences of the Interaction of Syntenin-1 with CD63{triangledown}

Nadya Latysheva,1,¶ Gairat Muratov,1,¶ Sundaresan Rajesh,1,¶ Matthew Padgett,1 Neil A. Hotchin,2 Michael Overduin,1 and Fedor Berditchevski1*

Cancer Research UK Institute for Cancer Studies,1 School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom2

Received 12 May 2006/ Returned for modification 13 June 2006/ Accepted 7 August 2006

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 localized 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 stabilizing 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 internalization of the tetraspanin. Furthermore, internalization 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 internalized via AP-2-dependent mechanisms. Hence, our data indicate that syntenin-1 can counteract the AP-2-dependent internalization and identify this tandem PDZ protein as a new regulator of endocytosis.

* Corresponding author. Mailing address: CR UK Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414 2801. Fax: 44-121-414 4486. E-mail: f.berditchevski{at}bham.ac.uk.

{triangledown} Published ahead of print on 14 August 2006.

These authors equally contributed to this work.

Molecular and Cellular Biology, October 2006, p. 7707-7718, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00849-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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