The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8
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DOI：
10.1101/gad.606911
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发表时间：
2011-01-15
影响因子：
10.5
通讯作者：
Llorca, Oscar
中科院分区：
文献类型：
--
作者：
Arias-Palomo, Ernesto;Yamashita, Akio;Llorca, Oscar
无义介导的mRNA衰变（NMD）是一种真核生物监控途径，它调节含有过早翻译终止密码子的mRNA的降解。NMD还影响许多生理转录物的表达。SMG-1是NMD必需的一个大激酶，磷酸化Upf1，这似乎是触发mRNA衰变的决定性信号。然而，SMG-1激酶活性的调控仍然知之甚少。本研究揭示了SMG-1与SMG-8和SMG-9复合物的三维结构，以及调控SMG-1激酶的结构机制。在SMG-1的N端，包含一长段HEAT（亨廷顿延伸因子3，PP2A和TOR1的亚基）重复序列的弯曲臂作为SMG-8和SMG-9的支架，并从含有磷脂酰肌醇3-激酶结构域的c端核心伸出。SMG-9似乎通过将SMG-8募集到SMG-1的n端HEAT重复区间接控制SMG-1的活性。值得注意的是，SMG-8结合SMG-1: SMG-9复合物特异性地下调了Upf1上SMG-1的激酶活性，而不接触催化结构域。SMG-1: SMG-8: SMG-9复合物的组装诱导了向激酶结构域发出信号的HEAT重复的显著运动。因此，smg -9介导的募集后，SMG-8诱导的大规模构象变化调节了SMG-1激酶活性，从而调节了NMD。
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG-1 is a large kinase essential to NMD that phosphorylates Upf1, which seems to be the definitive signal triggering mRNA decay. However, the regulation of the kinase activity of SMG-1 remains poorly understood. Here, we reveal the three-dimensional architecture of SMG-1 in complex with SMG-8 and SMG-9, and the structural mechanisms regulating SMG-1 kinase. A bent arm comprising a long region of HEAT (huntington, elongation factor 3, a subunit of PP2A and TOR1) repeats at the N terminus of SMG-1 functions as a scaffold for SMG-8 and SMG-9, and projects from the C-terminal core containing the phosphatidylinositol 3-kinase domain. SMG-9 seems to control the activity of SMG-1 indirectly through the recruitment of SMG-8 to the N-terminal HEAT repeat region of SMG-1. Notably, SMG-8 binding to the SMG-1: SMG-9 complex specifically down-regulates the kinase activity of SMG-1 on Upf1 without contacting the catalytic domain. Assembly of the SMG-1: SMG-8: SMG-9 complex induces a significant motion of the HEAT repeats that is signaled to the kinase domain. Thus, large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate NMD.