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”, which often reside in the acceptor stem and anticodon. These identity elements are highly conserved throughout evolution. For example, almost all known alanine tRNA (tRNAAla) isoacceptors contain a G3:U70 wobble base pair in the acceptor stem that identifies tRNAAla for aminoacylation with alanine. Transfer of this GU base pair into a non-alanine tRNA efficiently converts it into an alanine acceptor. On the contrary, mutation of the anticodon of tRNAAla does not compromise its identity as an alanine acceptor. Sequence and 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 recognition of the canonical identity elements G3:U70. Surprisingly, these two amino acid residues are absent from human mitochondrial AlaRS (AlaRSm or AARS2). Even more surprising was the finding that human mitochondrial tRNAAla (tRNAmAla) lacks G3:U70. As a result, AARS2 failed to charge tRNAAla with G3:U70 (unpublished data). This raised the question of how AARS2 recognizes its cognate tRNA. Moreover, a recent study showed that a homozygous mutation or compound heterogeneous mutations in human AARS2 cause infantile mitochondrial cardiomyopathy. However, the molecular mechanism underlying this disease is still elusive. The proposal presented herein elaborates a three-year project, in which we aim (1) to study how human AARS2 recognizes a noncanonical tRNAAla (without G3:U70), and (2) to study how human AARS2 mutations cause infantile mitochondrial cardiomyopathy (CM).
|Effective start/end date||1/08/20 → 31/07/21|
UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):
- aminoacyl-tRNA synthetase
- identity elements
- infantile mitochondrial cardiomyopathy
- protein synthesis
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