H-ras protein in a bilayer: interaction and structure perturbation.
Ras GTPases become functionally active when anchored to membranes by inserting their lipid modified side chains. Their role in cell division, development, and cancer has made them targets of extensive research efforts, yet the mechanism of membrane insertion and the structure of the resulting complex remain elusive. Recently, the structure of the full-length H-ras protein in a DMPC bilayer has been computationally characterized. Here, the atomic interactions between the H-ras membrane anchor and the DMPC bilayer are investigated in detail. We find that the palmitoylated cysteines and Met182 have dual contributions to membrane affinity: hydrogen bonding by their amides and van der Waals interaction by their hydrophobic side chains. The polar side chains help maintain the orientation of the anchor. Although the overall structure of the bilayer is similar to that of a pure DMPC, there are localized perturbations. These perturbations depend on the insertion depth and backbone localization of the anchor, which in turn is modulated by the catalytic domain and the linker. The pattern of anchor amide-DMPC phosphate/carbonyl hydrogen bonds and the flexibility of Palm184 are important in discriminating between different modes of ras-DMPC interactions. The results provide structural arguments in support of the proposed participation of ras in the organization of membrane nanoclusters.
Gorfe
Alemayehu A
AA
Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, and Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0365, USA.
Babakhani
Arneh
A
McCammon
J Andrew
JA
D002462:Cell Membrane / Q000737:chemistry; D003198:Computer Simulation; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry*; D006860:Hydrogen Bonding; D008051:Lipid Bilayers / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D018631:ras Proteins / Q000737:chemistry*
D008051:Lipid Bilayers; D008565:Membrane Proteins; D018631:ras Proteins; D004134:Dimyristoylphosphatidylcholine