Repressor binding to a dorsal regulatory site traps human eIF4E in a high cap‐affinity state
Repressor binding to a dorsal regulatory site traps human eIF4E in a high cap‐affinity state
复制标题
阻遏蛋白与背侧调节位点的结合使人 eIF4E 处于高帽亲和力状态
作者：
M. Ptushkina;T. von der Haar;M. M. Karim;J. Hughes;J. McCarthy
真核生物翻译起始涉及被称为真核生物起始因子4F（eIF 4F）的帽结合复合物识别细胞mRNA的5′端。起始是信号转导通路介导的基因表达调控的关键点。我们研究了被称为4 E结合蛋白（4 E-BPs）的可调控阻遏物抑制人eIF 4 E功能的分子相互作用。eIF 4F的两个基本组成部分是帽结合蛋白eIF 4 E和eIF 4G，eIF 4G是一种结合eIF 4 E和其他必需eIFs的多功能蛋白。我们发现，4 E-BP 1和2通过竞争与eIF 4 E背侧位点的结合来阻断eIF 4G和eIF 4 E之间的相互作用。值得注意的是，4 E-BP在该背侧位点的结合通过腹侧帽结合槽增强帽结合，从而将eIF 4 E捕获在对加帽mRNA具有高亲和力的非活性复合物中。4 E-BP 1/2和eIF 4 E之间相互作用的结合接触和亲和力是不同的（4 E-BP 1和2的估计Kd值分别为10−8和3×10−9），这些特性的差异由保守基序中的三个氨基酸决定。这些数据提供了一个新的翻译调控的分子模型的定量框架。
Eukaryotic translation initiation involves recognition of the 5′ end of cellular mRNA by the cap‐binding complex known as eukaryotic initiation factor 4F (eIF4F). Initiation is a key point of regulation in gene expression in response to mechanisms mediated by signal transduction pathways. We have investigated the molecular interactions underlying inhibition of human eIF4E function by regulatable repressors called 4E‐binding proteins (4E‐BPs). Two essential components of eIF4F are the cap‐binding protein eIF4E, and eIF4G, a multi‐functional protein that binds both eIF4E and other essential eIFs. We show that the 4E‐BPs 1 and 2 block the interaction between eIF4G and eIF4E by competing for binding to a dorsal site on eIF4E. Remarkably, binding of the 4E‐BPs at this dorsal site enhances cap‐binding via the ventral cap‐binding slot, thus trapping eIF4E in inactive complexes with high affinity for capped mRNA. The binding contacts and affinities for the interactions between 4E‐BP1/2 and eIF4E are distinct (estimated Kd values of 10−8 and 3×10−9 for 4E‐BP1 and 2, respectively), and the differences in these properties are determined by three amino acids within an otherwise conserved motif. These data provide a quantitative framework for a new molecular model of translational regulation.
影响因子：
56.9
作者：
LIN, TA;KONG, XM;LAWRENCE, JC
通讯作者：
LAWRENCE, JC
影响因子：
10.5
作者：
Gingras, AC;Kennedy, SG;Hay, N
通讯作者：
Hay, N
影响因子：
2.9
作者：
Fletcher, CM;McGuire, AM;Wagner, G
通讯作者：
Wagner, G