Jenkins Kirsten, Mateeva Teodora, Szabó István, Melnik Andre, Picotti Paola, Csikász-Nagy Attila, Rosta Edina
Randall Division of Cell and Molecular Biophysics, Institute for Mathematical and Molecular Biomedicine, King's College London, London SE1 1UL, UK.
Department of Chemistry, King's College London, London SE1 1DB, UK.
Comput Struct Biotechnol J. 2020 Apr 22;18:1032-1042. doi: 10.1016/j.csbj.2020.04.010. eCollection 2020.
Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases hallmarked by the formation of toxic protein aggregates. However, targeting these aggregates therapeutically have thus far shown no success. The treatment of AD has remained particularly problematic since no new drugs have been approved in the last 15 years. Therefore, novel therapeutic targets need to be identified and explored. Here, through the integration of genomic and proteomic data, a set of proteins with strong links to α-synuclein-aggregating neurodegenerative diseases was identified. We propose 17 protein targets that are likely implicated in neurodegeneration and could serve as potential targets. The human phosphatidylinositol 5-phosphatase synaptojanin-1, which has already been independently confirmed to be implicated in Parkinson's and Alzheimer's disease, was among those identified. Despite its involvement in PD and AD, structural aspects are currently missing at the molecular level. We present the first atomistic model of the 5-phosphatase domain of synaptojanin-1 and its binding to its substrate phosphatidylinositol 4,5-bisphosphate (PIP). We determine structural information on the active site including membrane-embedded molecular dynamics simulations. Deficiency of charge within the active site of the protein is observed, which suggests that a second divalent cation is required to complete dephosphorylation of the substrate. The findings in this work shed light on the protein's binding to phosphatidylinositol 4,5-bisphosphate (PIP) and give additional insight for future targeting of the protein active site, which might be of interest in neurodegenerative diseases where synaptojanin-1 is overexpressed.
帕金森病（PD）、阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）是神经退行性疾病，其特征是形成有毒蛋白质聚集体。然而，迄今为止，针对这些聚集体进行治疗尚未取得成功。由于在过去15年中没有新药获批，AD的治疗一直特别棘手。因此，需要确定和探索新的治疗靶点。在这里，通过整合基因组和蛋白质组数据，鉴定出一组与α-突触核蛋白聚集性神经退行性疾病有密切联系的蛋白质。我们提出了17个可能与神经退行性变有关的蛋白质靶点，它们有可能成为潜在靶点。人类磷脂酰肌醇5-磷酸酶突触素-1已被独立证实与帕金森病和阿尔茨海默病有关，它就在这些被鉴定出的蛋白质之中。尽管它与帕金森病和阿尔茨海默病有关，但目前在分子水平上还缺少其结构方面的信息。我们展示了突触素-1的5-磷酸酶结构域及其与底物磷脂酰肌醇4,5-二磷酸（PIP）结合的首个原子模型。我们通过包括膜嵌入分子动力学模拟在内的方法确定了活性位点的结构信息。观察到该蛋白质活性位点内电荷不足，这表明需要第二个二价阳离子来完成底物的去磷酸化。这项工作的发现揭示了该蛋白质与磷脂酰肌醇4,5-二磷酸（PIP）的结合情况，并为未来靶向该蛋白质活性位点提供了更多见解，这在突触素-1过度表达的神经退行性疾病中可能会引起关注。
