溶液中ATAD2溴结构域聚集行为的研究

The Aggregation of ATAD2 Bromodomain in Solution

三磷酸腺苷酶家族蛋白2(ATAD2)是一种染色质调节因子.它的异常表达与多种恶性肿瘤的发生和发展密切相关,因此还被称为致癌转录辅助因子.ATAD2由ATP酶结构域和溴结构域组成.其中,溴结构域可以特异性识别并结合组蛋白末端的乙酰化赖氨酸位点,调控染色体重构和转录,但其功能相关的很多结构特征并未可知.我们首先发现ATAD2溴结构域在溶液中易发生聚集.然后以核磁共振(NMR)和圆二色谱(CD)为主要研究手段,从环境因素和结构因素两方面对ATAD2溴结构域的聚集机理进行了初步探讨,发现该聚集行为伴有结构变化,并可能与功能相关.本研究可能为ATAD2溴结构域抑制剂的研发提供新的思路.

ATPase family AAA domain-containing protein 2(ATAD2)is a chromatin regulator,also known as an oncogenic transcription cofactor.Its abnormal expression is closely related to the occurrence and development of various malignant tumors.ATAD2 consists of two domains:the ATPase domain and the bromodomain.The bromodomain can specifically recognize and interact with the acetylated lysines in proteins,which regulates the refactoring and transcription of chromosomes.In this work,we found that ATAD2 bromodomains are aggregated under normal solution conditions.Considering the possible impact of aggregation on the interaction between ATAD2 bromodomain and acetylated histone tail,we preliminarily investigated the aggregation of ATAD2 bromodomains mainly by nuclear magnetic resonance(NMR)and circular dichroism(CD)spectra.The results suggested that the aggregation is accompanied with structure alteration and possibly related to the physiological functions of cells.This study may provide new clues for the development of ATAD2 bromodomain inhibitors.