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3-Dimensional architecture of the human multi-tRNA synthetase complex.
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2020-07-09 , DOI: 10.1093/nar/gkaa569
Krishnendu Khan 1 , Camelia Baleanu-Gogonea 2 , Belinda Willard 3 , Valentin Gogonea 2 , Paul L Fox 1
Affiliation  

In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). AARSs have critical roles in interpretation of the genetic code during protein synthesis, and in non-canonical functions unrelated to translation. Nonetheless, the structure and function of the MSC remain unclear. Partial or complete crystal structures of all MSC constituents have been reported; however, the structure of the holo-MSC has not been resolved. We have taken advantage of cross-linking mass spectrometry (XL-MS) and molecular docking to interrogate the three-dimensional architecture of the MSC in human HEK293T cells. The XL-MS approach uniquely provides structural information on flexibly appended domains, characteristic of nearly all MSC constituents. Using the MS-cleavable cross-linker, disuccinimidyl sulfoxide, inter-protein cross-links spanning all MSC constituents were observed, including cross-links between eight protein pairs not previously known to interact. Intra-protein cross-links defined new structural relationships between domains in several constituents. Unexpectedly, an asymmetric AARS distribution was observed featuring a clustering of tRNA anti-codon binding domains on one MSC face. Possibly, the non-uniform localization improves efficiency of delivery of charged tRNA’s to an interacting ribosome during translation. In summary, we show a highly compact, 3D structural model of the human holo-MSC.

中文翻译:

人多tRNA合成酶复合物的3维结构。

在哺乳动物细胞中,八种胞质氨酰基-tRNA合成酶(AARS)和三种非合成酶蛋白驻留在大型的多tRNA合成酶复合物(MSC)中。AARS在蛋白质合成过程中的遗传密码解释中以及与翻译无关的非规范功能中起着至关重要的作用。尽管如此,MSC的结构和功能仍不清楚。已经报道了所有MSC成分的部分或全部晶体结构;但是,holo-MSC的结构尚未解决。我们已经利用交联质谱(XL-MS)和分子对接技术来研究人HEK293T细胞中MSC的三维结构。XL-MS方法可以唯一地提供有关灵活附加域的结构信息,这几乎是所有MSC组件的特征。使用MS可裂解的交联剂二琥珀酰亚胺基亚砜,观察到了跨所有MSC成分的蛋白间交联,包括以前未知相互作用的八个蛋白对之间的交联。蛋白质内交联定义了几种成分中结构域之间的新结构关系。出乎意料的是,观察到不对称的ARS分布,其特征是在一个MSC面上聚集了tRNA反密码子结合域。可能的是,不均匀的定位提高了翻译过程中将带电tRNA传递至相互作用的核糖体的效率。总而言之,我们展示了人类全息MSC的高度紧凑的3D结构模型。包括之前未知的八种蛋白质对之间的交联。蛋白质内交联定义了几种成分中结构域之间的新结构关系。出乎意料的是,观察到不对称的ARS分布,其特征是在一个MSC面上聚集了tRNA反密码子结合域。可能的是,不均匀的定位提高了翻译过程中将带电tRNA传递至相互作用的核糖体的效率。总而言之,我们展示了人类全息MSC的高度紧凑的3D结构模型。包括之前未知的八种蛋白质对之间的交联。蛋白质内交联定义了几个组成部分之间的新结构关系。出乎意料的是,观察到不对称的ARS分布,其特征是在一个MSC面上聚集了tRNA反密码子结合域。可能的是,不均匀的定位提高了翻译过程中将带电tRNA传递至相互作用的核糖体的效率。总而言之,我们展示了人类全息MSC的高度紧凑的3D结构模型。非均匀的定位提高了翻译过程中带电tRNA传递至相互作用核糖体的效率。总而言之,我们展示了人类全息MSC的高度紧凑的3D结构模型。非均匀的定位提高了翻译过程中带电tRNA传递至相互作用核糖体的效率。总而言之,我们展示了人类全息MSC的高度紧凑的3D结构模型。
更新日期:2020-09-05
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