Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene
Structural basis for a human glycosylation disorder caused by mutation of the COG4 gene
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DOI：
10.1073/pnas.0901966106
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发表时间：
2009-08-11
影响因子：
11.1
通讯作者：
Hughson, Frederick M.
中科院分区：
文献类型：
--
作者：
Richardson, Brian C.;Smith, Richard D.;Hughson, Frederick M.
通过高尔基体运输的蛋白质的适当糖基化依赖于保守的寡聚高尔基体（COG）复合物。COG缺陷可导致人类致命的先天性糖基化障碍（CDG）。最近发现的CDG的一种形式，部分原因是由一个COG 4错义突变改变精氨酸729色氨酸，促使我们确定1.9埃的晶体结构的Cog 4 C-末端片段。发现Arg 729占据盐桥网络中心的关键位置，从而稳定Cog 4的小C-末端结构域。在HeLa细胞中的研究表明，该C-末端结构域，虽然不需要将Cog 4并入COG复合物，但对于细胞表面蛋白的适当糖基化是必不可少的。我们还发现，Cog 4具有很强的结构相似的外囊和Dsl 1 p复合物亚基。这些复合物和其他已被提议通过介导运输囊泡和它们的膜靶之间的初始拴系来发挥作用;新出现的结构相似性提供了共同进化起源的强有力证据，并可能反映了共同的作用机制。
The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 angstrom crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action.