YARS2 Human

The YARS2 gene is located on chromosome 12p11.21 and spans approximately 8.6 kb, containing five exons . The gene encodes a protein of 477 amino acids, which includes a 16-amino acid mitochondrial targeting signal . This signal directs the enzyme to the mitochondria, where it performs its function.

YARS2 catalyzes the attachment of tyrosine to tRNA^Tyr in a two-step reaction:

1. Activation of Tyrosine: Tyrosine is first activated by ATP to form tyrosyl-adenylate (Tyr-AMP).
2. Transfer to tRNA: The activated tyrosine is then transferred to the acceptor end of tRNA^Tyr .

This reaction is critical for the proper functioning of the mitochondrial protein synthesis machinery. The enzyme’s activity ensures that tyrosine is correctly incorporated into mitochondrial proteins, which are essential for various cellular processes, including energy production.

Mutations in the YARS2 gene are associated with a rare genetic disorder known as Myopathy, Lactic Acidosis, and Sideroblastic Anemia 2 (MLASA2) . This condition is characterized by muscle weakness, lactic acidosis, and anemia due to defective mitochondrial protein synthesis. Patients with MLASA2 often exhibit symptoms such as exercise intolerance, muscle cramps, and fatigue.

Recombinant YARS2 has been extensively studied to understand its structure and function. For instance, studies have shown that recombinant YARS2 can aminoacylate purified E. coli tRNA^Tyr and in vitro transcribed human mitochondrial tRNA^Tyr . Additionally, gel-filtration chromatography has demonstrated that recombinant YARS2 forms dimers, which is important for its enzymatic activity .

The crystal structure of YARS2 has provided insights into its catalytic mechanism and its interaction with tRNA. These studies have also revealed how YARS2 and other aminoacyl-tRNA synthetases can acquire new functions and evolve to bind multiple structurally related RNAs .