脆性X 综合征是世界范围内最常见的遗传性智力缺陷疾病，主要是由脆性X智力低下蛋白（fragile X mental retardation protein, FMRP）功能缺陷导致。近年来多个研究表明FMRP蛋白参与干细胞的命运调控，是维持干细胞和抑制分化所必需的，但其结构基础仍不清楚。FMRP可以结合多种RNA、甲基化组蛋白、核糖体、mRNP以及其它蛋白。目前只解出FMRP几个片段结构，而FMRP发挥复杂生物学功能的结构基础不清楚，因此研究其结构与功能的关系非常重要。.本项目在已发表的论文及前期重大课题资助下开展的工作基础上，将通过生物化学、体内外实验、分子生物学和结构生物学等技术，研究FMRP识别不同核酸、多位点修饰组蛋白和其它蛋白的复合物结构和生化机理，提出并验证其对底物的特征结合模式，深入探讨干细胞中FMRP发挥生物学功能的机制，为干细胞的定向分化、疾病药物设计和开发等提供结构基础

Fragile X syndrome, the most common genetic neurodevelopmental disorder, is caused by deficiency of the fragile X mental retardation protein (FMRP). Recently, a number of new studies showed that FMRP is involved in regulating the fate of stem cells. FMRP is essential for stem cell maintenance and for the inhibition of stem cell differentiation. However, the structural basis remains poorly understood. FMRP can bind many kinds of RNA, methylated histone, ribosome, mRNP and other proteins. Only several fragments of FMRP were solved, and understanding how FMRP regulates stem cell and function remains a major challenge. Therefore, it is very important to uncover the relation of structure- and function of FMRP.. In this project, based on our previous publication and the preliminary results supported by NSFC, we will determine several FMRP structures complexed with different nucleic acids, multiple modified histones and other proteins using protein crystallography. And we will reveal the function of FMRP in stem cell maintenance and differentiation combining with biochemical, in vitro and in vivo experiments, molecular biology studies. Furthermore, we will uncover and verify the binding mode of the substrates by FMRP. All these results will be of great significance to understand the molecular mechanism of FMRP in stem cell research. The results will also provide a direction for development of new materials and new medicines in stem cell differentiation and diseases.

脆性X 综合征是世界范围内最常见的遗传性智力缺陷疾病，主要是由脆性X智力低下蛋白（fragile X mental retardation protein, FMRP）功能缺陷导致。近年来多个研究表明FMRP蛋白参与干细胞的命运调控，是维持干细胞和抑制分化所必需的，但其结构基础仍不清楚。FMRP可以结合多种RNA、甲基化组蛋白、核糖体、mRNP以及其它蛋白。目前只解出FMRP几个片段结构，而FMRP发挥复杂生物学功能的结构基础不清楚，因此研究其结构与功能的关系非常重要。在本基金的资助下，围绕项目的计划，本项目对FMRP的底物进行筛选和复合物结构的解析与功能研究方面，取得一些富有意义的成果，培养高素质的研究生10人。标有本课题资助、以通信作者或共同通信作者发表的SCI论文有2篇，还有2篇在投。本工作进行 FMRP 识别组蛋白翻译后修饰的研究，微量热泳动实验和等温滴定量热实验证明 FMRP N 端结构域结合一个新的、三修饰多肽, 且其C 端不含修饰的氨基酸残基对其的结合能力是必需的，解析出几个在这个修饰多肽存在下的FMRP蛋白结构，为阐明 FMRP 在细胞中的功能提供了新的实验依据，为干细胞的定向分化、疾病药物设计和开发等提供结构基础。