Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites
Direct functional interaction of initiation factor eIF4G with type 1 internal ribosomal entry sites
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DOI：
10.1073/pnas.0900153106
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发表时间：
2009-06-09
影响因子：
11.1
通讯作者：
Hellen, Christopher U. T.
中科院分区：
文献类型：
--
作者：
de Breyne, Sylvain;Yu, Yingpu;Hellen, Christopher U. T.
病毒内部核糖体进入位点（IRES）介导末端非依赖性翻译起始。有4个主要的结构不同的IRES组：1型（e。例如，在一个实施例中，脊髓灰质炎病毒）和2型（e.例如，在一个实施例中，脑心肌炎病毒），它们除了在它们的3'边界处的Yn-Xm-AUG基序之外是不同的，3型（e.例如，在一个实施例中，丙型肝炎病毒）和4型（双顺反子病毒）。2-4型IRES通过不同的机制介导起始，然而这些机制都是基于与翻译装置的典型组分的特异性非典型相互作用，例如真核起始因子（eIF）4G（2型），40 S核糖体亚基（3型和4型）和eIF 3（3型）。1型IRES的启动机制尚不清楚。我们现在报告，结构域V的1型IRES，这是相邻的Yn-Xm-AUG基序，特别是与eIF 4G的中央结构域相互作用。eIF 4G相对于Yn-Xm-AUG基序的位置和方向在1型和2型IRES中是类似的。eIF 4G促进eIF 4A募集至1型IRES，并且eIF 4G和eIF 4A一起诱导其3'边界处的构象变化。突变型1 IRES结合eIF 4G/eIF 4A的能力与其翻译活性相关。这些特征与2型IRES的起始机制相似，其中关键事件是eIF 4G与邻近Yn-Xm-AUG基序的J-K结构域结合，这被eIF 4A增强。这些数据表明，这些不相关类别的IRES的启动机制的基本方面是相似的。
Viral internal ribosomal entry sites (IRESs) mediate end-independent translation initiation. There are 4 major structurally-distinct IRES groups: type 1 (e. g., poliovirus) and type 2 (e. g., encephalomyocarditis virus), which are dissimilar except for a Yn-Xm-AUG motif at their 3' borders, type 3 (e. g., hepatitis C virus), and type 4 (dicistroviruses). Type 2-4 IRESs mediate initiation by distinct mechanisms that are nevertheless all based on specific noncanonical interactions with canonical components of the translation apparatus, such as eukaryotic initiation factor (eIF) 4G (type 2), 40S ribosomal subunits (types 3 and 4), and eIF3 (type 3). The mechanism of initiation on type 1 IRESs is unknown. We now report that domain V of type 1 IRESs, which is adjacent to the Yn-Xm-AUG motif, specifically interacts with the central domain of eIF4G. The position and orientation of eIF4G relative to the Yn-Xm-AUG motif is analogous in type 1 and 2 IRESs. eIF4G promotes recruitment of eIF4A to type 1 IRESs, and together, eIF4G and eIF4A induce conformational changes at their 3' borders. The ability of mutant type 1 IRESs to bind eIF4G/eIF4A correlated with their translational activity. These characteristics parallel the mechanism of initiation on type 2 IRESs, in which the key event is binding of eIF4G to the J-K domain adjacent to the Yn-Xm-AUG motif, which is enhanced by eIF4A. These data suggest that fundamental aspects of the mechanisms of initiation on these unrelated classes of IRESs are similar.