STRUCTURAL BASIS OF PP1 REGULATION BY SPINOPHILIN

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The production of smooth, voluntary motions is a consequence of the rapid and precise processing of incoming sensory signals into outgoing motor responses. Much of this processing occurs within specialized cells of the striatum, medium spiny neurons (MSN), whose activity is regulated by the opposing actions of glutamate (excitatory), g-aminobutyric acid (inhibitory; GABA) and dopamine (modulatory) neurotransmitters. It is the integration of these signals in MSNs which leads to precise muscle control, and imbalances in these signaling pathways are characteristic of numerous motor disorders, including Huntington's chorea and Parkinson's disease. Studies have implicated a central role for the protein serine/threonine phosphatase (PSP) protein phosphatase-l (PP1) in MSN signal integration, as it is a target of both the glutamatergic and dopaminergic signaling pathways. A novel PP1 targeting/scaffolding protein, spinophilin, which localizes PP1 to dendritic spines, has recently been identified. In addition to binding PP1, spinophilin also binds actin filaments and D2 dopamine receptors. The presence of these independent domains within a single protein makes spinophilin uniquely structured to link the PP1 phosphatase signaling cascades to the proteins of the cytoskeleton and the ion channels of the synapse, thus providing a molecular basis for postsynaptic signal integration. Crystallographic studies of the individual spinophilin domains, both alone and complexed to their binding partners, will be carried out to elucidate the structural basis of PP1 localization and activity modulation by phosphatase targeting proteins. Structural information obtained from such a study could then be used to design drugs which function to disrupt the PP1:PP1-targeting subunit interactions-drugs which may be potential therapies for the motor disorders of Huntington's chorea and Parkinson's disease.