Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling
Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling
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DOI：
10.1038/nature06173
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发表时间：
2007-10-18
期刊：
影响因子：
64.8
通讯作者：
McMahon, Harvey T.
中科院分区：
文献类型：
--
作者：
Daumke, Oliver;Lundmark, Richard;McMahon, Harvey T.
响应于核苷酸水解而主动重塑膜的能力在很大程度上归因于发动蛋白超家族的GTP酶，并且这些已经被广泛研究（1）。含Eps 15同源性（EH）结构域的蛋白质（EHD/RME-1/pincher）包括一类特征不太清楚的高度保守的真核ATP酶，其涉及网格蛋白非依赖性内吞作用（2）和从内体再循环（3，4）。在这里，我们表明，EHD与发动蛋白超家族有许多共同的特点，如对核苷酸的低亲和力，在体外微管脂质体的能力，低聚化周围的环状结构的脂质小管和刺激的核苷酸水解响应脂质结合。我们提出了EHD 2的结构，绑定到一个不可水解的ATP类似物，并提供证据与EHDs在体内核苷酸依赖性膜重塑的作用一致。核苷酸结合结构域参与二聚化，其在二聚体中产生高度弯曲的膜结合区域。二聚体的寡聚化发生在核苷酸结合结构域的另一个界面上，这使我们能够模拟EHD寡聚体。我们讨论了EHD 2结构的功能意义，了解膜变形。
The ability to actively remodel membranes in response to nucleotide hydrolysis has largely been attributed to GTPases of the dynamin superfamily, and these have been extensively studied(1). Eps15 homology (EH)-domain-containing proteins (EHDs/RME-1/pincher) comprise a less-well-characterized class of highly conserved eukaryotic ATPases implicated in clathrin-independent endocytosis(2), and recycling from endosomes(3,4). Here we show that EHDs share many common features with the dynamin superfamily, such as a low affinity for nucleotides, the ability to tubulate liposomes in vitro, oligomerization around lipid tubules in ring-like structures and stimulated nucleotide hydrolysis in response to lipid binding. We present the structure of EHD2, bound to a non-hydrolysable ATP analogue, and provide evidence consistent with a role for EHDs in nucleotide-dependent membrane remodelling in vivo. The nucleotide-binding domain is involved in dimerization, which creates a highly curved membrane-binding region in the dimer. Oligomerization of dimers occurs on another interface of the nucleotide-binding domain, and this allows us to model the EHD oligomer. We discuss the functional implications of the EHD2 structure for understanding membrane deformation.