Fig. 5. ksr3 is an ancient gene present in most non-chordate phyla and the structure of KSR3 factors resembles that of oncogenic human RAF mutants.
a Maximum likelihood phylogenetic analysis of KSR and RAF sequences showing that ksr3 sequences constitute an ancient family of genes conserved in metazoans. Numbers represent bootstrap values calculated from a consensus of 1000 replicates77, 78 (see Supplementary data Fig. 1 for a detailed tree). b ksr1/2 and ksr3 gene complement across metazoans. Numbers indicate the presence and number of ksr1/2 and ksr3 genes. Asterisks indicate that a complete ksr complement could not be confidently determined. Note that ksr3 has been lost in chordates as well as in nematodes and insects. Also note that the nematode and human ksr1 and ksr2 genes are in fact recent duplications of an ancestral ksr1 gene. c Schematic representation of the structure of human KSR1, human KSR2, human B-RAF and of KSR3 protein from sea urchin. In humans, most oncogenic mutations map to specific regions of B-RAF such as the P-loop, the alpha C helix, the dimerization interface and the activation segment. d Frequency of positions in KSR3 that differ from B-RAF within the set of 19 KSR3 sequences selected for the analysis. KSR factors mainly diverge from B-RAF at the level of the P-loop, the alpha C helix, the dimerization interface, the catalytic loop and the activation segment. The sequence of human B-RAF is shown as a reference. The histogram shows the percentage of divergence compared to B-RAF.