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Membrane Composition and Raf[CRD]-Membrane Attachment Are Driving Forces for K-Ras4B Dimer Stability
Ioannis Andreadelis1, Sofia Kiriakidi1, Christos Lamprakis1
1Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527 Athens, Greece.
The Journal of Physical Chemistry. B
|February 10, 2022
Summary
Anionic lipids influence K-Ras4B dimer stability and orientation on cell membranes. High anionic lipid concentrations enhance dimer stability, especially without Raf effectors, while Raf[CRD] anchoring is key when effectors are present.
Area of Science:
- Molecular Biology
- Biophysics
- Computational Biology
Background:
- Ras proteins are GTPases crucial for cellular signaling.
- Anionic lipids affect Ras dimerization and clustering on cell membranes.
- Understanding K-Ras4B's spatiotemporal properties is vital for deciphering signaling pathways.
Purpose of the Study:
- To investigate the impact of anionic lipids on the spatiotemporal properties of dimeric K-Ras4B.
- To simulate K-Ras4B dimerization on model anionic lipid membranes with varying lipid compositions.
- To analyze the influence of Raf effectors on K-Ras4B dimer stability and membrane interactions.
Main Methods:
- All-atom molecular dynamics simulations of dimeric K-Ras4B.
- Utilized two model anionic lipid membranes with different DOPC, DOPS, and PIP2 concentrations.
- Employed Markov state modeling to identify dominant K-Ras4B conformations and orientations.
Main Results:
- Dimeric K-Ras4B stability is enhanced on membranes with higher anionic lipid concentrations, particularly without Raf effectors.
- Raf[RBD/CRD] effectors enhance dimer stability, with stability influenced by Raf[CRD] membrane anchoring rather than lipid concentration.
- Correlations observed between K-Ras4B diffusion, PIP2, and anionic lipid anchoring to the Raf[CRD] domain.
Conclusions:
- Both membrane composition and Raf effector interactions, specifically Raf[CRD] anchoring, modulate K-Ras4B dimer conformational stability.
- These interactions are critical for maintaining essential interface interactions in K-Ras4B signaling.
- Findings provide insights into the regulation of K-Ras4B dimerization by membrane environment and effectors.
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