人類粒線體AARS2的tRNA專一性及其突變引發嬰兒心肌症的機制研究;Study of the Trna Specificity of Human Mitochondrial Aars2 and Its Connection to Infantile Mitochondrial Cardiomyopathy

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Title:	人類粒線體AARS2的tRNA專一性及其突變引發嬰兒心肌症的機制研究;Study of the Trna Specificity of Human Mitochondrial Aars2 and Its Connection to Infantile Mitochondrial Cardiomyopathy
Authors:	王健家
Contributors:	國立中央大學生命科學系
Keywords:	蛋白質合成;轉譯作用;tRNA;分子演化;嬰兒心肌症;aminoacyl-tRNA synthetase;infantile mitochondrial cardiomyopathy;protein synthesis;translation;tRNA
Date:	2020-01-13
Issue Date:	2020-01-13 14:15:18 (UTC+8)
Publisher:	科技部
Abstract:	Aminoacyl-tRNA synthetases (aaRSs)是一群必要的轉譯酵素，它們的主要功能是將胺基酸接到相對應的tRNA (胺醯化)，形成aminoacyl-tRNA，接著aminoacyl-tRNA會被延長因子攜帶至核醣體進行蛋白質合成。aaRS主要是透過tRNA上的識別決定基(identity elements)來辨認相對應的tRNA，並維持專一性。tRNA的識別決定基多數集中在acceptor stem及anticodon loop。相同專一性的tRNA通常具有相同或相似的識別決定基，不會因來源不同而有所差異，例如Alanine tRNA (tRNAAla)的識別決定基是在acceptor stem上的G3:U70鹼基配對，對幾乎所有物種的tRNAAla而言，G3:U70都是最重要且唯一的識別決定基。如果改變tRNAAla的G3:U70，它就無法被alanyl-tRNA synthetase (AlaRS)辨認及胺醯化；相反地，如果改變tRNAAla的反密碼，並不影響其胺醯化效率。序列比對及三級結構分析顯示：AlaRS的tRNA結合位置上有二個高度保留的胺基酸(Asp及Asn)，這二個胺基酸專門負責辨認G3:U70。令人驚訝的是人類粒線體AlaRS (AlaRSm) (由AARS2基因解碼)的相對應位置上並非Asp及Asn，更令人驚訝的是人類粒線體tRNAAla (tRNAmAla)上並沒有G3:U70，我們的胺醯化實驗顯示：人類粒線體AlaRS不會辨認具有G3:U70的tRNAAla (未發表初步結果)。另外，最近有研究報告指稱人類粒線體AlaRS突變會引起嬰兒心肌症，但是詳細機制尚不清楚。為了解開這些謎團，我們擬定了一個三年期的研究計畫，重點包括：(1)研究人類粒線體AlaRS如何辨認自己的tRNAAla (沒有G3:U70)；(2)研究人類粒線體AlaRS突變為何會導致嬰兒心肌症。 ;Aminoacyl-tRNA synthetases (aaRSs) are a family of translation enzymes, each of which catalyzes the attachment of a specific amino acid to its cognate tRNAs. Each tRNA is recognized by its cognate aaRS through a specific set of “identity elements” located on its structure. Alanine tRNA (tRNAAla) is unique among tRNAs for having a G3:U70 wobble base pair in the acceptor stem that identifies tRNAAla for aminoacylation with alanine. This wobble pair is conserved in almost all known tRNAAla isoacceptors. Transfer of this GU base pair into a non-alanine tRNA efficiently converts it to an alanine acceptor. On the contrary, transfer of the anticodon of a non-alanine tRNA into tRNAAla does not alter its identity as an alanine acceptor. Structural studies show that two highly conserved amino acid residues, Asp and Asn, in the tRNA-binding domain of alanyl-tRNA synthetase (AlaRS) are responsible for specific recognition of the G3:U70 base pair. Surprisingly, these two amino acid residues are absent from human mitochondrial AlaRS (AlaRSm) (encoded by AARS2). Even more surprising was the finding that human mitochondrial tRNAAla (tRNAmAla) lacks the universal identity elements G3:U70 and human AlaRSm cannot charge tRNAAla with G3:U70 (unpublished data). This raised the question of how human AlaRSm recognizes its cognate tRNA. Moreover, a recent study showed that a homozygous mutation or compound heterogeneous mutations in human AARS2 (encoding AlaRSm) cause infantile mitochondrial cardiomyopathy. However, the underlying mechanism causing this disease is still elusive. The proposal presented herein elaborates a three-year project, in which we aim (1) to study how human AlaRSm recognizes its cognate tRNAmAla, and (2) to study how human AlaRSm mutations cause infantile mitochondrial cardiomyopathy.
Relation:	財團法人國家實驗研究院科技政策研究與資訊中心
Appears in Collections:	[Department of Life Science] Research Project

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