STRUCTURAL BASIS OF PP1 REGULATION BY SPINOPHILIN

流畅、随意运动的产生是将传入的感官信号快速而精确地处理为传出的运动反应的结果。这种处理大部分发生在纹状体的特殊细胞中，即中棘神经元(MSN)，其活动受到谷氨酸(兴奋性)、g-氨基丁酸(抑制性；GABA)和多巴胺(调制)神经递质的相反作用的调节。正是这些信号在MSN中的整合导致了精确的肌肉控制，而这些信号通路中的失衡是许多运动障碍的特征，包括亨廷顿舞蹈症和帕金森氏病。研究表明，蛋白质丝氨酸/苏氨酸磷酸酶-L(PP1)在MSN信号整合中起着核心作用，因为它是谷氨酸和多巴胺能信号通路的靶标。最近发现了一种新的PP1靶向/支架蛋白，SPINOPHILIN，它将PP1定位于树突棘。除了结合PP1，亲刺蛋白还结合肌动蛋白细丝和D2多巴胺受体。这些独立结构域在单个蛋白质中的存在使得亲棘素具有独特的结构，将PP1磷酸酶信号级联到突触的细胞骨架和离子通道的蛋白质上，从而为突触后信号整合提供了分子基础。为了阐明PP1定位和磷酸酶靶向蛋白活性调节的结构基础，我们将对单独的和与其结合伙伴络合的单个Spin-phinin结构域进行结晶学研究。从这样的研究中获得的结构信息然后可以用来设计能够破坏PP1的药物：PP1-靶向亚单位相互作用-这可能是治疗亨廷顿舞蹈症和帕金森病运动障碍的潜在药物。

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.