Methionine 170 is an Environmentally Sensitive Membrane Anchor in the Disordered HVR of K-Ras4B

Area of Science:

• Molecular Biophysics
• Cell Biology
• Computational Biology

Background:

• Ras proteins are crucial for cell signaling, regulating growth, survival, and motility.
• Ras protein localization to the plasma membrane is essential for activating these signaling pathways.
• The precise mechanisms driving Ras self-association and membrane interaction remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms governing K-Ras4B membrane interactions and self-association.
• To investigate the role of the C-terminal membrane tether in regulating Ras protein behavior.
• To understand how membrane composition influences Ras nanoclustering and effector binding.

Main Methods:

• Utilized molecular dynamics (MD) simulations to model K-Ras4B C-terminal membrane tether interactions.
• Analyzed the influence of basic and hydrophobic residues on membrane association.
• Investigated the impact of anionic lipids and local membrane composition on Ras protein states and nanoclustering.

Main Results:

• Anionic lipids attract lysine residues, leading to two distinct peptide populations on the membrane surface.
• These populations exhibit microsecond-scale exchange and differ in methionine residue membrane insertion, influenced by lipid composition.
• Anionic lipids promote K-Ras4B tether association via electrostatic screening, but short-range clustering is not driven by direct interpeptide contact.

Conclusions:

• The C-terminal membrane tether of K-Ras4B dynamically regulates membrane interactions through distinct states.
• Membrane composition, particularly anionic lipids, influences these states and K-Ras4B's propensity to nanocluster.
• Observed K-Ras4B nanoclustering is likely an indirect consequence of lipid interactions, not direct tether-tether binding, impacting effector accessibility.