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J. Biol. Chem., Vol. 279, Issue 30, 31002-31009, July 23, 2004

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Microtubule-associated Protein Light Chain 2 Is a Stargazin-AMPA Receptor Complex-interacting Protein in Vivo^*

Jane H. Ives, Susanna Fung, Priyanka Tiwari, Helen L. Payne, and Christopher L. Thompson

From the School of Biological and Biomedical Sciences, Science Research Laboratories, University of Durham, South Road, Durham DH1 3LE, United Kingdom

The ataxic mutant mouse stargazer is a null mutant for stargazin, a protein involved in the regulation of cell surface trafficking and synaptic targeting of AMPA receptors. The extreme C terminus of stargazin (sequence, –TTPV), confers high affinity for PDZ domain-containing proteins e.g. PSD-95. Interaction with PDZ proteins enables stargazin to fulfill its role as an AMPA receptor synaptic targeting molecule but is not essential for its ability to influence AMPA receptor trafficking to the neuronal cell surface. Using the yeast-two hybrid approach we screened for proteins that interact with the intracellular C-terminal tail of stargazin. Positive interactors included PDZ domain-containing proteins e.g. SAP97, SAP102, and PIST. Interestingly, light chain 2 of microtubule-associated protein 1 (LC2), which does not contain a PDZ domain, was also a strong interactor. This was shown to be a direct interaction that occurred upstream of the -TTPV sequence of stargazin. Immunoprecipitations of Triton X-100 soluble cerebellar extracts revealed that LC2 is pulled down not only by anti-stargazin antibodies but also anti-GluR2 antibodies suggesting that stargazin and AMPA receptor subunits associate with LC2. Immunopurified full-length, native stargazin was shown to co-associate not only with GluR2 in vivo but also with full-length, native LC2. Indeed, LC2 co-associates with stargazin when part of a tripartite complex comprising LC2-stargazin-GluR2. Since this complex was extracted using Triton X-100 and was devoid of PSD95, SAP97, and actin we postulate that LC2 is involved in trafficking of AMPA receptors in cerebellar neurons before they are anchored at the synapse.

Received for publication, February 27, 2004 , and in revised form, May 7, 2004.

^* This work was supported by Grants 0543478 and 066204 from the Wellcome Trust, Grant 12/C19310 from the Biotechnology and Biological Sciences Research Council, and AstraZeneca UK Ltd. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: School of Biological and Biomedical Sciences, University of Durham, Science Research Laboratories, South Rd., Durham DH1 3LE, UK. Tel.: 44-191-334-1291; Fax: 44-191-334-1201; E-mail: C.L.Thompson{at}durham.ac.uk.

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