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The Journal of Neuroscience, October 20, 2004, 24(42):9391-9404; doi:10.1523/JNEUROSCI.3314-04.2004

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Cellular/Molecular
A Functional Role of Postsynaptic Density-95-Guanylate Kinase-Associated Protein Complex in Regulating Shank Assembly and Stability to Synapses

Stefano Romorini,¹ Giovanni Piccoli,¹ Ming Jiang,³ Pasquale Grossano,¹ Noemi Tonna,¹ Maria Passafaro,^1,2 Mingjie Zhang,³ and Carlo Sala¹

¹Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, ²Dulbecco Telethon Institute, 20129 Milan, Italy, and ³Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

Postsynaptic density (PSD) proteins include scaffold, cytoskeletal, and signaling proteins that structurally and functionally interact with glutamate receptors and other postsynaptic membrane proteins. The molecular mechanisms regulating the assembly of PSD proteins and their associations with synapses are still widely unknown. We investigated the molecular mechanisms of Shank1 targeting and synapse assembly by looking at the function of guanylate kinase-associated protein (GKAP) and PSD-95 interactions. Shank1 when it is not associated to GKAP, which binds to the Shank PSD-95-Discs Large-zona occludens-1 domain, forms filamentous and fusiform structures in which the Src homology 3 domain specifically interacts with the ankyrin repeat domain, thus allowing its multimerization via a novel form of intermolecular interaction. Surprisingly, in both COS-7 cells and hippocampal neurons, GKAP forms insoluble aggregates with Shank that colocalize with heat shock protein 70 and neurofilaments, two markers of the aggresomes in which misfolded proteins accumulate. However, the two proteins are organized in clusters in COS cells and synaptic clusters in neurons when both are overexpressed and associated with wild-type PSD-95, but not with palmitoylation-deficient PSD-95. Synaptic activity in neurons induces the formation of Shank and GKAP intracellular aggregation and degradation. Similarly, the overexpression of a GKAP mutant that is incapable of binding PSD-95 induces Shank aggregation and degradation in neurons. Our data suggest a possible functional and structural role of the PSD-95-GKAP complex in Shank and PSD protein assembly and stability to synapses.

Key words: postsynapstic density; aggresomes; cytoskeleton; PDZ domain; Homer; intermediate filaments

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Received March 1, 2004; revised September 7, 2004; accepted September 9, 2004.

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