The inner circle shows an HVR adopting a number of conformations, the middle circle represents mechanisms whereby the HVR can modulate signalling and the outer circle describes how this modulation can affect signalling. Middle circle: (Top) Models of K-Ras-4B·GDP (in orange) K-Ras-4B·GTP (in blue) interacting with the surface of a nanodisc, PDB codes 2MSC, 2MSD, respectively [127]. The effector binding region is shown as spheres: with the change in nucleotide there is a change in orientation with respect to the membrane. (Right) Interaction of the HVR of K-Ras-4B (magenta) with PDE-δ (green), PDB code 5TB5 [120]. (Bottom) Schematic representing the change in dynamics of the HVR of K-Ras-4B in response to phosphorylation at Ser181 as proposed by Zhou and colleagues [39].The unmodified HVR exists as a population with varying degrees of disorder (O = ordered, I = intermediate, D = disordered), phosphorylation causes a shift in population to the disordered state which favours interaction with PIP₂ lipids instead of phosphatidylserine (PS). (Left) Schematic showing the macroorganization of Ras proteins into discrete membrane domains, which results from the differential sorting abilities of the HVR. K-Ras-4B (orange dots) cluster in domains enriched with PS lipids to potentiate MAPK signalling through C-Raf activation, while H-Ras (blue dots) clusters into separate domains enriched in PIP₂ and increases signalling through PI3K.