Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex.
Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex.
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DOI：
10.1093/nar/gkab414
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发表时间：
2021-06-21
影响因子：
14.9
通讯作者：
Weichenrieder O
中科院分区：
文献类型：
--
作者：
Chen Y;Khazina E;Izaurralde E;Weichenrieder O
CCR4和CAF1 deadenylase物理相互作用形成CCR4-CAF1复合物，并作为更大的CCR4- not复合物的催化核心。它们共同负责从基本上所有细胞mrna中最终去除3 ' -poly(A)尾巴，因此在基因表达的转录后调控中发挥核心作用。然而，CCR4和CAF1的个体特性以及它们在不同生物体和细胞环境中的各自作用尚不完全清楚。在这里，我们确定了人类CCR4-CAF1复合物的晶体结构，并表征了其酶和底物识别特性。该结构揭示了影响RNA结合和水解的特定分子细节，并证实CCR4核酸酶结构域在两个酶活性位点之间有相当距离的情况下被灵活地拴在一起。CCR4和CAF1在3 '端磷酸的两侧识别核苷酸，有效区分单个和连续的非a残基。与CCR4相比，CAF1是一种令人惊讶的可调节酶，对pH、镁和锌离子高度敏感，可能允许不同的反应几何形状。我们的研究结果支持了CAF1作为一种原始deadenylase的观点，它得到CCR4的辅助以提高效率，并通过组装的NOT蛋白选择性靶向和调控mRNA。
The CCR4 and CAF1 deadenylases physically interact to form the CCR4-CAF1 complex and function as the catalytic core of the larger CCR4-NOT complex. Together, they are responsible for the eventual removal of the 3′-poly(A) tail from essentially all cellular mRNAs and consequently play a central role in the posttranscriptional regulation of gene expression. The individual properties of CCR4 and CAF1, however, and their respective contributions in different organisms and cellular environments are incompletely understood. Here, we determined the crystal structure of a human CCR4-CAF1 complex and characterized its enzymatic and substrate recognition properties. The structure reveals specific molecular details affecting RNA binding and hydrolysis, and confirms the CCR4 nuclease domain to be tethered flexibly with a considerable distance between both enzyme active sites. CCR4 and CAF1 sense nucleotide identity on both sides of the 3′-terminal phosphate, efficiently differentiating between single and consecutive non-A residues. In comparison to CCR4, CAF1 emerges as a surprisingly tunable enzyme, highly sensitive to pH, magnesium and zinc ions, and possibly allowing distinct reaction geometries. Our results support a picture of CAF1 as a primordial deadenylase, which gets assisted by CCR4 for better efficiency and by the assembled NOT proteins for selective mRNA targeting and regulation.
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影响因子：
14.9
作者：
Abshire ET;Chasseur J;Bohn JA;Del Rizzo PA;Freddolino PL;Goldstrohm AC;Trievel RC
通讯作者：
Trievel RC
影响因子：
4
作者：
Alseth, Ingrun;Dalhus, Bjorn;Bjoras, Magnar
通讯作者：
Bjoras, Magnar
影响因子：
5.6
作者：
Cheng, Y;Patel, DJ
通讯作者：
Patel, DJ
影响因子：
11.4
作者：
BEESE, LS;STEITZ, TA
通讯作者：
STEITZ, TA
影响因子：
5.6
作者：
Chen, JJ;Rappsilber, J;Denis, CL
通讯作者：
Denis, CL