Alternative splicing creates two new architectures for human tyrosyl-tRNA synthetase

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Human tRNA synthetases possess non-canonical functions beyond protein synthesis.
• Over 200 splice variants (SVs) of tRNA synthetases exist, many lacking catalytic activity and enabling new biological roles.
• Limited understanding of protein structures arising from natural internal deletions in synthetases.

Purpose of the Study:

• To investigate the structural consequences of internal deletions in human tyrosyl-tRNA synthetase (TyrRS).
• To analyze the biochemical and structural properties of two related, internally deleted TyrRS splice variants.
• To explore the potential for neomorphic functions and tissue-specific expression of these variants.

Main Methods:

• Biochemical analysis of TyrRS splice variants.
• Nuclear Magnetic Resonance (NMR) spectroscopy to determine protein structures.
• Analysis of dimerization interfaces and protein quaternary structure.

Main Results:

• Two internally deleted TyrRS splice variants (TyrRSΔE2-4 and TyrRSΔE2-3) fold into distinct, stable structures despite ablating parts of the catalytic core and native dimer interface.
• TyrRSΔE2-4 forms a novel, neomorphic dimer interface independent of the native one.
• TyrRSΔE2-3, due to a C-terminal splice site, is predominantly monomeric and lacks both native and neomorphic dimerization.
• Both variants exhibit distinct tissue-specific expression patterns, unlike the ubiquitous native TyrRS.

Conclusions:

• Human tRNA synthetases exhibit remarkable structural plasticity, allowing for significant architectural reorganization through internal deletions.
• Internally deleted splice variants can adopt unique stable structures, including neomorphic dimerization interfaces.
• These structural adaptations are associated with tissue-specific expression, suggesting specialized non-translational roles.