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Published on: April 26, 2024
Molecular trigger for pre-transfer editing pathway in Valyl-tRNA synthetase: a molecular dynamics simulation study
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China.
Journal of Molecular Modeling
|June 1, 2010
Summary
The pre-transfer editing pathway in Valyl-tRNA synthetase (ValRS) ensures protein synthesis accuracy. Molecular dynamics simulations reveal how noncognate Thr-AMP binding triggers this editing pathway via specific domain motions and salt-bridge alterations.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Protein synthesis fidelity is crucial for cellular function.
- The pre-transfer editing pathway in Valyl-tRNA synthetase (ValRS) is vital for accuracy.
- The molecular mechanisms underlying this editing pathway remain largely unknown.
Purpose of the Study:
- To elucidate the molecular basis of the pre-transfer editing pathway in ValRS.
- To understand how the noncognate substrate Thr-AMP triggers this pathway.
- To compare the dynamics of ValRS with cognate (Val-AMP) and noncognate (Thr-AMP) substrates.
Main Methods:
- Molecular dynamics (MD) simulations were performed on two complexes: ValRS·tRNA(val)·Val-AMP and ValRS·tRNA(val)·Thr-AMP.
- Simulation trajectories were compared to identify differences in protein dynamics.
- Key residue motions and salt-bridge formations/dissociations were analyzed.
Main Results:
- Binding of Thr-AMP induced distinct motions in ValRS, including editing domain rotation and catalytic domain movements, particularly in the KMSKS loop.
- A conformational change in Trp495, triggered by Thr-AMP, acts as a discrimination signal.
- This signal propagates through the (491)ILFL(494) segment, leading to salt-bridge disruption (Asp490-Arg346) and formation (Glu189-Lys533), altering domain dynamics and initiating pre-transfer editing.
Conclusions:
- A molecular model for the trigger of the ValRS pre-transfer editing pathway by noncognate substrates is proposed.
- Specific protein dynamics and salt-bridge rearrangements mediate substrate discrimination and pathway activation.
- This study provides insights into maintaining protein synthesis fidelity and potential targets for further research.
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