Structural basis of oligomerization in the stalk region of dynamin-like MxA
Structural basis of oligomerization in the stalk region of dynamin-like MxA
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DOI：
10.1038/nature08972
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发表时间：
2010-05-27
期刊：
影响因子：
64.8
通讯作者：
Daumke, Oliver
中科院分区：
文献类型：
--
作者：
Gao, Song;von der Malsburg, Alexander;Daumke, Oliver
干扰素诱导的动力蛋白样粘病毒抗性蛋白1（MxA;也称为MX 1）GTdR是针对病原体（如流感病毒）的细胞自主先天免疫的关键介质（1）。MxA部分定位于滑面内质网-高尔基体中间室的COPI阳性膜（2）。在感染时，它会重新分布到病毒复制位点，并促进病毒基本成分的错误分类（3，4）。已经提出动力蛋白样GTP酶的中间结构域和GTP酶效应结构域构成了一个茎，其介导寡聚化并将构象变化从G结构域传递到靶结构（5-7）;然而，该茎的分子结构仍然难以捉摸。在这里，我们报告的晶体结构的柄的人MxA，折叠成一个四螺旋束。这种结构在晶体中紧密地低聚，以十字交叉的模式，涉及三个不同的界面和一个环。这些相互作用位点中的每一个中的突变干扰MxA的天然组装、寡聚化、膜结合和抗病毒活性。在这些结果的基础上，我们提出了一个结构模型，动力蛋白寡聚化和刺激GTP水解，是与以前的结构预测一致，并具有功能的影响，动力蛋白家族的所有成员。
The interferon-inducible dynamin-like myxovirus resistance protein 1 (MxA; also called MX1) GTPase is a key mediator of cell-autonomous innate immunity against pathogens such as influenza viruses(1). MxA partially localizes to COPI-positive membranes of the smooth endoplasmic reticulum-Golgi intermediate compartment(2). At the point of infection, it redistributes to sites of viral replication and promotes missorting of essential viral constituents(3,4). It has been proposed that the middle domain and the GTPase effector domain of dynamin-like GTPases constitute a stalk that mediates oligomerization and transmits conformational changes from the G domain to the target structure(5-7); however, the molecular architecture of this stalk has remained elusive. Here we report the crystal structure of the stalk of human MxA, which folds into a four-helical bundle. This structure tightly oligomerizes in the crystal in a criss-cross pattern involving three distinct interfaces and one loop. Mutations in each of these interaction sites interfere with native assembly, oligomerization, membrane binding and antiviral activity of MxA. On the basis of these results, we propose a structural model for dynamin oligomerization and stimulated GTP hydrolysis that is consistent with previous structural predictions and has functional implications for all members of the dynamin family.