核多聚腺嘌呤结合蛋白 (PABPN1) 是存在于哺乳动物细胞核内的RNA结合蛋白，其N-端的丙氨酸序列延伸突变可能造成该蛋白质发生错误折叠并形成淀粉样积聚，导致遗传性眼咽部肌肉萎缩症。本申请项目拟研究PABPN1蛋白的生化特性、结构基础、RNA结合、积聚以及募集RNA结合蛋白的机制。我们将阐明(1) PABPN1中的N-端丙氨酸丰富序列是否为积聚核心; (2) RRM结构域与RNA的识别作用，(3) PABPN1积聚物对其它RNA结合蛋白的募集作用。通过研究蛋白质分子在细胞中的行为深入认识PABPN1的积聚与细胞毒性或退行性的关系。该研究成果将为进一步理解PABPN1及其它RNA结合蛋白的致病机制提供依据。

Poly(A) binding protein nuclear 1 (PABPN1) is an RNA-binding protein locating in the nuclei of mammalian cells. Expansion of Ala-rich region in the N terminus of PABPN1 is proposed to cause misfolding and amyloid aggregation that may lead to a disease of oculopharyngeal muscular dystrophy. In this project, we will investigate the biochemical properties of PABPN1 and their structural bases, including RNA-binding, amyloid aggregation and sequestration of RNA-binding proteins. We will realize (1) whether the Ala-rich sequence is the amyloidogenic core of PABPN1 aggregation; (2) how the RRM domain recognizes RNA sequences; and (3) how the PABPN1 aggregates sequester RNA-binding proteins. By study of the protein in molecular and cellular levels, we will understand the relationship between PABPN1 aggregation and the cell toxicity or degeneration. The research will provide fundamental information for further deciphering pathologies of the degenerative diseases caused by PABPN1 and other RNA-binding proteins.