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. Author manuscript; available in PMC: 2017 Jan 1.
Published in final edited form as: Cancer Res. 2015 Dec 10;76(1):18–23. doi: 10.1158/0008-5472.CAN-15-1536

Figure 1.

Figure 1

K-Ras4A is in-between K-Ras4B and N-Ras. (a) The human KRAS gene encodes two splice variants of the K-Ras protein, K-Ras4A and K-Ras4B. K-Ras4A and K-Ras4B are identical in their first 150 amino acid residues, and subject to the same oncogenic mutations at positions 12, 13, and 61 (denoted in red). However, they differ in their C-terminal hypervariable region (HVR) and in four residues (151, 153, 165, and 166) at the edges of helix 5 in the catalytic domain, adjoining the membrane. The four residue substitutions between K-Ras4A and K-Ras4B are highlighted in maroon and blue respectively. (b) The HVR of the K-Ras4A isoform contains a bipartite polybasic region, PBR1 and PBR2. K-Ras4B’s HVR has a highly charged polybasic domain, with an additional charged patch between the polybasic regions. K-Ras4B is farnesylated, and K-Ras4A and N-Ras are farnesylated and palmitoylated. H-Ras is fanesylated and doubly palmitoylated. Basic residues are colored in blue, acidic residues in red, hydrophobic residues in black and polar and glycine residues in green. Farnesylated cysteine residues are denoted by an orange lipid group, whereas the reversibly palmitoylated cysteine residues are denoted by green lipid groups. (c) In the N-Ras-like state (left), the K-Ras4A hypervariable region (HVR) is both palmitoylated and farnesylated, whereas in the K-Ras4B-like state (right), the K-Ras4A HVR is only farnesylated. As denoted by the red lipid head groups (negatively charged phospholipids) the composition of the plasma membrane differs between them: zwitterionic, in the case of the N-Ras-like state and anionic liquid membrane in the case of the K-Ras4B-like state. Basic residues (blue stretches) in the K-Ras4A HVR interact more favorably with the negatively charged phospholipid head groups of the plasma membrane (on the right) - though not as favorably as the more positively charged HVR of K-Ras4B. The lower positive charge of K-Ras4A allows interaction with zwitterionic membranes (on the left) - though not as favorably as the neutral N-Ras. The four catalytic domain residues that differ between K-Ras4A and K-Ras4B are shown in stick form.