Structure of the catalytic fragment of translation initiation factor 2B and identification of a critically important catalytic residue
Structure of the catalytic fragment of translation initiation factor 2B and identification of a critically important catalytic residue
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DOI：
10.1074/jbc.m311055200
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发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Andersen, GR
中科院分区：
文献类型：
--
作者：
Boesen, T;Mohammad, SS;Andersen, GR
真核起始因子（eIF）2B催化eIF 2的核苷酸活化至其活性GTP结合状态。交换活性已被定位到eIF 2B β亚基的C末端。我们已经在2.3埃分辨率下确定了酵母eIF 2B的残基544 - 704的晶体结构，并且该片段是围绕在eIF 4G和eIF 5中也发现的保守的芳香酸（AA）盒构建的全螺旋蛋白。八个螺旋以类似于HEAT重复的方式组织。该分子在表面电荷和守恒方面是高度不对称的。在N末端的一个区域被认为是直接参与催化。与这一假设一致，谷氨酸569突变被证明是致命的。C末端的酸性带和含有AA盒残基的第二个区域对于与eIF 2的结合很重要。两个突变导致致命的人类遗传性疾病白质脑病消失的白色物质被掩埋，似乎破坏了催化结构域的结构完整性，而不是直接干扰催化或结合eIF 2。
Eukaryotic initiation factor (eIF) 2B catalyzes the nucleotide activation of eIF2 to its active GTP-bound state. The exchange activity has been mapped to the C terminus of the eIF2Bepsilon subunit. We have determined the crystal structure of residues 544 - 704 from yeast eIF2Bepsilon at 2.3-Angstrom resolution, and this fragment is an all-helical protein built around the conserved aromatic acidic ( AA) boxes also found in eIF4G and eIF5. The eight helices are organized in a manner similar to HEAT repeats. The molecule is highly asymmetric with respect to surface charge and conservation. One area in the N terminus is proposed to be directly involved in catalysis. In agreement with this hypothesis, mutation of glutamate 569 is shown to be lethal. An acidic belt and a second area in the C terminus containing residues from the AA boxes are important for binding to eIF2. Two mutations causing the fatal human genetic disease leukoencephalopathy with vanishing white matter are buried and appear to disrupt the structural integrity of the catalytic domain rather than interfering directly with catalysis or binding of eIF2.