Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Aminoacyl-tRNA synthetases (AARSs) are primarily known for their cytoplasmic role in protein synthesis.
• Emerging evidence indicates AARSs possess critical extracellular and nuclear functions.
• Evolutionary adaptation may lead to splice variants with altered domain structures.

Purpose of the Study:

• To investigate the structural and functional consequences of an internally deleted histidyl-tRNA synthetase (HisRSΔCD) variant.
• To understand how the absence of the catalytic domain impacts AARS structure and potential function.
• To explore evolutionary pressures driving AARS structural diversification.

Main Methods:

• X-ray crystallography to determine high-resolution structures.
• Three-dimensional Nuclear Magnetic Resonance (3D NMR) spectroscopy for structural analysis.
• Biochemical characterization of the HisRSΔCD variant.

Main Results:

• An expressed 171-amino acid HisRSΔCD variant lacking the catalytic domain was identified.
• HisRSΔCD exists as a monomer, unlike the homodimeric wild-type HisRS.
• Structural analysis revealed a dumbbell-like conformation with flexibly linked N-terminal WHEP and C-terminal anticodon-binding domains (ABD), and a distinct local conformation in the ABD.

Conclusions:

• The HisRSΔCD variant demonstrates significant structural rearrangement due to catalytic domain deletion.
• This natural variant provides insights into AARS structural plasticity and evolutionary repurposing.
• Altered AARS structures may facilitate novel extracellular or nuclear functions.