SFPQ is a ubiquitous nuclear RNA-binding protein implicated in many aspects of RNA biogenesis. Importantly, nuclear depletion and cytoplasmic accumulation of SFPQ has been linked to neuropathological conditions such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here, we describe a molecular mechanism by which SFPQ is mislocalized to the cytoplasm. We report an unexpected discovery of the infinite polymerization of SFPQ that is induced by zinc binding to the protein. The crystal structure of human SFPQ in complex with zinc at 1.94 Å resolution reveals intermolecular interactions between SFPQ molecules that are mediated by zinc. As anticipated from the crystal structure, the application of zinc to primary cortical neurons induced the cytoplasmic accumulation and aggregation of SFPQ. Mutagenesis of the three zinc-coordinating histidine residues resulted in a significant reduction in the zinc-binding affinity of SFPQ in solution and the zinc-induced cytoplasmic aggregation of SFPQ in cultured neurons. Taken together, we propose that dysregulation of zinc availability and/or localization in neuronal cells may represent a mechanism for the imbalance in the nucleocytoplasmic distribution of SFPQ, which is an emerging hallmark of neurodegenerative diseases including AD and ALS.

中文翻译：

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锌诱导的RNA结合蛋白SFPQ的胞质聚集的结构基础。

SFPQ是一种普遍存在的核RNA结合蛋白，涉及RNA生物发生的许多方面。重要的是，SFPQ的核耗竭和细胞质积累已与阿尔茨海默氏病（AD）和肌萎缩性侧索硬化症（ALS）等神经病理疾病相关。在这里，我们描述了SFPQ错位到细胞质的分子机制。我们报告了由锌与蛋白质结合诱导的SFPQ无限聚合的意外发现。人SFPQ与锌以1.94Å的复合物的晶体结构揭示了锌介导的SFPQ分子之间的分子间相互作用。如从晶体结构所预期的那样，将锌应用于初级皮层神经元可诱导SFPQ的细胞质积累和聚集。三个锌配位组氨酸残基的诱变导致溶液中SFPQ的锌结合亲和力显着降低，以及锌在培养的神经元中诱导的SFPQ胞质聚集。两者合计，我们建议失调锌可用性和/或在神经元细胞中的定位可能代表了SFPQ的核质分布不平衡的机制，这是神经退行性疾病包括AD和ALS的新兴标志。