Dimerization of elongator protein 1 is essential for Elongator complex assembly.
Dimerization of elongator protein 1 is essential for Elongator complex assembly.
复制标题
延伸蛋白 1 的二聚化对于延伸复合物的组装至关重要。
DOI：
10.1073/pnas.1502597112
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发表时间：
2015
影响因子：
11.1
通讯作者：
Long Jiafu
中科院分区：
文献类型：
--
作者：
Xu Huisha;Lin Zhijie;Li Fengzhi;Diao Wentao;Dong Chunming;Zhou Hao;Xie Xingqiao;Wang Zheng;Shen Yuequan;Long Jiafu
Significance Elongator is a highly conserved multiprotein complex composed of six subunits elongator protein 1 (Elp1 to -6). Elongator has been associated with various cellular activities and has attracted clinical attention because of its role in certain neurodegenerative diseases. To understand the mechanism of Elongator assembly, we identified the highly conserved dimerization domain in both human and yeast Elp1 subunits and solved the crystal structures of the dimerization domains. This study is a mechanistic analysis of Elp1 dimerization, which plays an essential role in the integrity of functional Elongator and suggests that the pathological mechanisms underlying the onset and progression of Elp1 mutation-related diseases may result from impaired Elongator activities. The evolutionarily conserved Elongator complex, which is composed of six subunits elongator protein 1 (Elp1 to -6), plays vital roles in gene regulation. The molecular hallmark of familial dysautonomia (FD) is the splicing mutation of Elp1 [also known as IκB kinase complex-associated protein (IKAP)] in the nervous system that is believed to be the primary cause of the devastating symptoms of this disease. Here, we demonstrate that disease-related mutations in Elp1 affect Elongator assembly, and we have determined the structure of the C-terminal portion of human Elp1 (Elp1-CT), which is sufficient for full-length Elp1 dimerization, as well as the structure of the cognate dimerization domain of yeast Elp1 (yElp1-DD). Our study reveals that the formation of the Elp1 dimer contributes to its stability in vitro and in vivo and is required for the assembly of both the human and yeast Elongator complexes. Functional studies suggest that Elp1 dimerization is essential for yeast viability. Collectively, our results identify the evolutionarily conserved dimerization domain of Elp1 and suggest that the pathological mechanisms underlying the onset and progression of Elp1 mutation-related disease may result from impaired Elongator activities.
