LOCALIZATION OF POSTSYNAPTIC DENSITY-93 TO DENDRITIC MICROTUBULES ANDINTERACTION WITH MICROTUBULE-ASSOCIATED PROTEIN 1A

Postsynaptic density-93 (PSD-93)/Chapsyn-110 is a member of the membra ne-associated guanylate kinase (MAGUK) family of PDZ domain-containing proteins. MAGUKs are widely expressed in the brain and are critical e lements of the cytoskeleton and of certain synapses. In the ultrastruc tural studies that are described here, PSD-93 localizes to both postsy naptic densities and dendritic microtubules of cerebellar Purkinje neu rons. The microtubule localization is paralleled by a high-affinity in vivo interaction of PSD-93 via its guanylate kinase (GK) domain with microtubule-associated protein 1A (MAP1A). GK domain truncations that mimic genetically identified mutations of a Drosophila MAGUK, discs-la rge, disrupt the GK/MAP-1A interaction. Additional biochemical experim ents demonstrate that intact MAGUKs do not bind to MAP1A as effectivel y as do isolated GK domains. This appears to be attributable to an int ramolecular inhibition of the GK domain by the PDZs, because GK bindin g activity of full-length MAGUKs is partially restored by a variety of PDZ ligands, including the C termini of NMDA receptor 2B, adenomatous polyposis coli (APC), and CRIPT. Beyond demonstrating a novel cytoske letal link for PSD-93, these experiments support a model in which intr amolecular interactions between the multiple domains of MAGUKs regulat e intermolecular associations and thereby may play a role in the prope r targeting and function of MAGUK proteins.