Adaptive recognition of a prokaryote-like tRNAPro by a eukaryote-like prolyl-tRNA synthetase

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拉蒂法(Emi Latifah) 查詢紙本館藏

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論文名稱

(Adaptive recognition of a prokaryote-like tRNAPro by a eukaryote-like prolyl-tRNA synthetase)

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摘要(中)

藉由分析三個域中的Prolyl-tRNA synthetase (ProRS)可以歸納出兩種不同的結構，真核生物/古生菌類型(E-type) ProRS和原核生物類型(P-type) ProRS，前者在C-terminal多一段domain，後者在motif 2和motif 3之間有一段額外的domain。除此之外，不同ProRS辨識的tRNAPro也有所不同，ProRS主要會辨識tRNAPro的anticodon和acceptor stem，雖然anticodon在所有生物中都非常保守，acceptor stem上的序列卻不太一樣，在細菌中是G72/A73，但在真核生物中是C72/C73，有趣的是，E. coli tRNAPro中的G72/A73是主要被辨識的序列，但在人類tRNAPro中C72/C73並不被辨識。令人訝異的是，有數種細菌被發現帶有E-type而非P-type的ProRS，例如嗜熱菌Thermus thermophilus，我們的實驗結果顯示這種細菌的E-type ProRS能夠辨識G72/A73，這顯示了T. thermophilus ProRS (TtProRS)儘管在結構上類似人類的ProRS，辨識的特性卻類似E. coli ProRS，會同時辨認anticodon上的G35/G36，和acceptor stem 上的G72/A73。然而，不同於典型P-type ProRS，TtProRS並不使用在motif 2 上非常保守的R胺基酸，而是使用同樣在motif 2中的RTR 序列，然而在典型的 E-type ProRS中RTR並不保守，這說明TtProRS從典型E-type發展出獨特的序列及辨識機制。此外，我們也發現TtProRS相對於其他E-type ProRS對 halofuginone (一種從febrifugine衍生而來的E-type ProRS抑制劑，結構類似於Pro-A76)耐受性較高，特性比較接近細菌類型的ProRS。這項研究顯示了一個不可或缺且非常保守的酵素能隨著環境變化適應新的受質。

摘要(英)

Analysis of prolyl-tRNA synthetase (ProRS) from three domains of life uncovers two separate architectures: a eukaryote/archaeon-like (E-type) ProRS, distinguished by a C-terminal extension domain, and a prokaryote-like (P-type) ProRS, distinguished by an insertion domain. Diversity also appears in tRNAPro as the substrate of ProRS. While the anticodon elements of tRNAPro are highly conserved among all organisms and important for aminoacylation, the acceptor stem elements have diverged, with G72/A73 conserved in bacteria and C72/C73 conserved in eukaryotes. In E. coli tRNAPro, G72/A73 are major determinants, whereas in humans, C72/C73 are dispensable. Paradoxically, several bacteria have been revealed to possess an E-type ProRS, with one example being Thermus thermophilus ProRS (TtProRS). This bacterial E-type ProRS has been reported to selectively charge the P- type tRNAPro with G72/A73. This investigation reveals that despite the structural similarity with human ProRS, TtProRS maintains a strong recognition towards the anticodon elements G35/G36 and the acceptor-stem elements G72/A73, similar to E. coli ProRS. However, instead of relying on the strictly conserved R residue in the motif 2 loop of P-type ProRS to recognize G72/A73, TtProRS accomplishes this using RTR, a divergent sequence found within the E-type ProRS motif 2 loop. Here we also demonstrate TtProRS′s relatively resistance to halofuginone, a synthetic inhibitor of eukaryote-type ProRS derived from febrifugine mimicking Pro-A76, a characteristic similar to that of bacterium-type ProRS. This study highlights the adaptability of a usually conserved essential enzyme to adjust to a new substrate.

關鍵字(中)

關鍵字(英)

★ aminoacyl-tRNA synthetase
★ halofuginone
★ identity element
★ protein synthesis
★ thermophilic bacterium
★ tRNA

論文目次

ABSTRACT i
ABSTRACT (IN CHINESE) II
ACKNOWLEDGEMENT III
TABLE OF CONTENTS IV
LIST OF FIGURES VI
LIST OF TABLES VII
ABBREVIATION VIII
CHAPTER I 1
INTRODUCTION 1
1.1 Aminoacyl-tRNA synthetase 1
1.2 Prolyl-tRNA synthetase 2
1.3 ProRS recognition towards tRNAPro 3
1.4 Thermus thermophilus ProRS and its tRNAPro 4
1.5 Specific aim 5
CHAPTER II 6
MATERIALS AND METHODS 6
2.1 Construction of plasmids 6
2.2 Rescue of the genetic loss of yeast PROS1 on 5-FOA 6
2.3 Rescue of the genetic loss of yeast PROS2 on YPG 7
2.4 Western blotting 7
2.5 Purification of Thermus thermophilus ProRS 7
2.6 Preparation of tRNA transcripts 8
2.7 Aminoacylation assay 8
2.8 Halofuginone inhibition assay 9
CHAPTER III 10
RESULTS 10
3.1 T. thermophilus ProRS is an E-type ProRS with a distinct motif 2 loop sequence 10
3.2 Optimum temperature for TtProRS activity in vitro 10
3.3 TtProRS evolved to recognize G72/A73 in the acceptor-stem 11
3.4 Motif 2 loop of TtProRS facilitates the recognition of the G72/A73 12
3.5 TtProRS can rescue the genetic loss of yeast PROS2, but not PROS1 13
3.6 TtProRS is relatively resistance towards halofuginone 14
CHAPTER IV 15
DISCUSSION 15
4.1 TtProRS is an E-type enzyme but recognize the acceptor stem 15
4.2 Motif 2 loop of TtProRS mediates the recognition of G72/A73 15
4.3 TtProRS shows less sensitivity toward HF compared to canonical E-type enzymes 16
4.4 TtProRS originated through horizontal gene transfer. 16
LIST OF FIGURES 18
LIST OF TABLES 36
REFERENCES 38
APPENDIX A 42
APPENDIX B 47

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指導教授

王健家(Chien-Chia Wang)

審核日期

2024-6-21

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