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Molecular modeling of c-erbB2 receptor dimerization: coiled-coil structure of wild and oncogenic transmembrane
N Garnier1, D Genest, J P Duneau
1Centre de Biophysique Moléculaire, CNRS, Université d'Orleans, France.
Abstract:
Dimerization models of c-erbB2 transmembrane domains (Leu651-Ile675) are studied by molecular mechanics and molecular dynamics simulations. Both wild and Glu mutated transmembrane helices exhibit the same relative orientation for favorable associations and dimerize preferentially in left-handed coiled-coil structures. The mutation point 659 belongs to the interfacing residues, and in the transforming domain, symmetric hydrogen bonds between Glu carboxylic groups stabilize the dimeric structure. The same helix packing found for the wild dimers, except side-chain-side-chain hydrogen bonds, suggests that the transmembrane domains dimerize according to similar process. Structural and energetical characterization of the models are presented.
Insights
The c-erbB2 transmembrane domains dimerize into left-handed coiled-coil structures. A Glu mutation at position 659 stabilizes these dimers via hydrogen bonds, influencing dimerization in cancer research.
Area of Science:
- Biophysics
- Computational Biology
- Molecular Modeling
Background:
- The c-erbB2 receptor tyrosine kinase plays a crucial role in cell proliferation and survival.
- Transmembrane domains are critical for receptor dimerization and signaling.
- Understanding c-erbB2 transmembrane domain dimerization is key to developing targeted cancer therapies.
Purpose of the Study:
- To investigate the dimerization models of c-erbB2 transmembrane domains.
- To analyze the structural and energetic characteristics of wild-type and mutated helices.
- To elucidate the role of specific mutations in stabilizing dimer formation.
Main Methods:
- Molecular mechanics simulations.
- Molecular dynamics simulations.
- Structural and energetic characterization of dimerization models.
Main Results:
- Both wild and Glu-mutated transmembrane helices exhibit similar relative orientations for dimerization.
- Dimerization preferentially occurs in left-handed coiled-coil structures.
- A Glu mutation at position 659, an interfacing residue, forms symmetric hydrogen bonds that stabilize the dimeric structure.
Conclusions:
- c-erbB2 transmembrane domains dimerize via a conserved mechanism involving left-handed coiled-coil formation.
- Specific mutations, like Glu at 659, can enhance dimer stability through hydrogen bonding.
- These findings provide insights into receptor assembly and potential therapeutic targets in cancer.