染色质重塑蛋白ATRX活性调控的分子机制

X连锁α地中海贫血/智力发育迟缓蛋白（ATRX）不仅是ATRX综合征关键性的病因蛋白，还与数种肿瘤的发生发展密切相关。ATRX蛋白作为SF2超家族中的一员，具有ATP依赖的染色质重塑活性，并在调控基因表达、DNA修复、维持染色质稳定性等方面都发挥至关重要的作用。对于ATRX结构研究的缓慢进展制约着对其发挥功能的分子机制的深入研究。. 本项目将以结构学为突破口，对染色质重塑蛋白ATRX及相关蛋白复合物展开系统性研究，致力于（1）揭示ATRX发挥ATPase活性的结构基础和分子机制，（2）阐述ATRX和核小体在分子水平上的整体架构和重塑机制，（3）探究ATRX蛋白活性调控的分子机制，（4）阐明相关疾病突变的致病机理。上述研究成果不仅为进一步研究ATRX参与各项基本生命活动的机制奠定了坚实的基础，还能为相关的疾病治疗提出新思路和新靶点。

Alpha Thalassemia/Mental developmental retardation, X-linked (ATRX) protein(ATRX) is a major etiological factor for ATRX syndrome. The mutations of ATRX have also been found in some cancers. As a member of the SF2 superfamily, ATRX has an ATP-dependent chromatin remodeling activity, and plays important roles in regulating gene expression, DNA repair, and maintaining the chromosome stability. The limited information on ATRX structure is the bottle-neck for understanding the molecular mechanisms of ATRX functions. . In this project, we plan to apply X-ray crystallography and cryo-EM techniques to reveal the structural features of ATRX and related protein complexes, such as ATRX-DNA and ATRX-nucleosome complexes. We will explore the following aspects of ATRX: (1) the structural basis and molecular mechanism of DNA-dependent ATPase activity of ATRX, (2) the overall architecture of ATRX-nucleosome complex and molecular mechanisms of nucleosome remodeling by ATRX, (3) the potential regulating elements for ATRX activity, (4) the pathogenic mechanism of related disease mutations. Our work will not only pave the way for further research on the mechanism of ATRX participating in various cellular processes, but also provide clues for drug design for related disease treatment。