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Structural and Dynamic Characterization of Mutated Keap1 for Varied Affinity toward Nrf2: A Molecular Dynamics
I-Chung Cheng1, Ya-Jyun Chen2, Chia-Wei Ku2
1Rehabilitation Division, Zuoying Armed Forces General Hospital , Kaohsiung, Taiwan.
Journal of Chemical Information and Modeling
|September 9, 2015
Summary
Keap1 mutations G364C and G430C disrupt the Keap1-Nrf2 interaction by altering electrostatic recognition, potentially linking to lung cancer. Other serine mutations do not significantly impact this interaction.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Keap1 protein regulates Nrf2 (Nuclear factor erythroid 2-related factor 2) under oxidative stress.
- Nrf2 activation leads to increased transcription of cytoprotective genes.
- Specific Keap1 gene variants (G364C) and somatic mutations (G430C) are linked to lung cancer by impairing Keap1-Nrf2 interaction.
Purpose of the Study:
- To investigate the structural and dynamic differences between wild-type (WT) Keap1 and six mutants.
- To understand the molecular basis for the impaired Keap1-Nrf2 interaction in G364C and G430C mutants.
- To compare the effects of G364C/G430C mutations with serine-to-alanine mutations (S363A, S508A, S555A, S602A).
Main Methods:
- Molecular dynamics (MD) simulations of unbound WT Keap1 and six mutants.
- Principal component analysis (PCA) of MD trajectories to assess dynamic diversity.
- Structural and dynamic analysis of residue interactions and hydrogen bond networks.
Main Results:
- G364C and G430C mutants showed increased mobility of D385, which moved towards R380, disrupting electrostatic recognition with Nrf2.
- The four serine-to-alanine mutants (S363A, S508A, S555A, S602A) did not alter the hydrogen bond network crucial for Nrf2 binding.
- These serine mutants maintained structural and dynamic integrity comparable to WT Keap1.
Conclusions:
- The G364C and G430C mutations impair Keap1-Nrf2 interaction through altered electrostatic interactions involving D385 and R380.
- Mutations at serine residues (S363A, S508A, S555A, S602A) do not significantly affect Keap1 structure, dynamics, or Nrf2 binding.
- Understanding these molecular mechanisms is crucial for investigating Keap1's role in lung cancer.
