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人线粒体丙氨酰-tRNA 合成酶对 G3-U70 非依赖性 tRNA 的识别。

The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase.

机构信息

State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.

School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.

出版信息

Nucleic Acids Res. 2019 Apr 8;47(6):3072-3085. doi: 10.1093/nar/gkz078.

DOI:10.1093/nar/gkz078
PMID:30952159
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6451123/
Abstract

Alanyl-tRNA synthetases (AlaRSs) from three domains of life predominantly rely on a single wobble base pair, G3-U70, of tRNAAla as a major determinant. However, this base pair is divergent in human mitochondrial tRNAAla, but instead with a translocated G5-U68. How human mitochondrial AlaRS (hmtAlaRS) recognizes tRNAAla, in particular, in the acceptor stem region, remains unknown. In the present study, we found that hmtAlaRS is a monomer and recognizes mitochondrial tRNAAla in a G3-U70-independent manner, requiring several elements in the acceptor stem. In addition, we found that hmtAlaRS misactivates noncognate Gly and catalyzes strong transfer RNA (tRNA)-independent pre-transfer editing for Gly. A completely conserved residue outside of the editing active site, Arg663, likely functions as a tRNA translocation determinant to facilitate tRNA entry into the editing domain during editing. Finally, we investigated the effects of the severe infantile-onset cardiomyopathy-associated R592W mutation of hmtAlaRS on the canonical enzymatic activities of hmtAlaRS. Overall, our results provide fundamental information about tRNA recognition and deepen our understanding of translational quality control mechanisms by hmtAlaRS.

摘要

丙氨酰-tRNA 合成酶（AlaRSs）来自生命的三个领域，主要依赖于 tRNAAla 的单个摆动碱基对 G3-U70 作为主要决定因素。然而，该碱基对在人线粒体 tRNAAla 中是不同的，而是具有易位的 G5-U68。人线粒体 AlaRS（hmtAlaRS）如何识别 tRNAAla，特别是在受体茎区域，仍然未知。在本研究中，我们发现 hmtAlaRS 是单体，以不依赖于 G3-U70 的方式识别线粒体 tRNAAla，需要受体茎中的几个元件。此外，我们发现 hmtAlaRS 错误激活非对应物 Gly 并催化强烈的 tRNA 非依赖性预转移编辑作用于 Gly。Arg663 是编辑活性位点之外的完全保守残基，可能作为 tRNA 易位决定因素，有助于 tRNA 在编辑过程中进入编辑结构域。最后，我们研究了 hmtAlaRS 的严重婴儿期起病的心肌病相关 R592W 突变对 hmtAlaRS 的典型酶活性的影响。总的来说，我们的结果提供了关于 tRNA 识别的基本信息，并加深了我们对 hmtAlaRS 翻译质量控制机制的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/717d569ca725/gkz078fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/26c667631008/gkz078fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/20db650cb5c1/gkz078fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/cd2387bc7cfe/gkz078fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/69f4931e9796/gkz078fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/9219182a0b2a/gkz078fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/717d569ca725/gkz078fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/26c667631008/gkz078fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/20db650cb5c1/gkz078fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/cd2387bc7cfe/gkz078fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/69f4931e9796/gkz078fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/9219182a0b2a/gkz078fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72db/6451123/717d569ca725/gkz078fig6.jpg

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