A mock phylogenetic tree (left) shows the evolution of ERK1/2 and other MAP kinases. ERK1/2, and their common ancestor (dark blue) cannot efficiently activate themselves through autophosphorylation. More ancient ancestors in the MAP kinase family (light blue) are capable of efficient autophosphorylation. A cartoon diagram (right) highlights the structural properties that differentiate MAP kinases that are capable of autophosphorylation (light blue) from those that cannot autophosphorylate themselves efficiently (dark blue). All protein kinases have a two-lobe structure with a catalytic cleft in the middle. Different parts of the kinase are connected by a spine. The loop in front of the catalytic cleft has to shift position for the enzyme to become active. This is driven by phosphorylation of that loop, either by another kinase or through autophosphorylation (shown as pink residues in the inactive form of the enzyme becoming red residues in the active form, with a concomitant change in the shape of the loop). Sang et al. have identified two mutations that could explain why ERK1/2 and their common ancestor (bottom right, dark blue) are different from other MAP kinases (top right, light blue): i) they have a polar amino acid (yellow, bottom) rather than a hydrophobic amino acid (orange, top) at a site near the spine of the kinase; ii) a loop above the catalytic cleft is one amino acid shorter than in other MAP kinases. It is thought that these two mutations disrupt the geometry and flexibility of the catalytic cleft, altering the ability of the kinase to autophosphorylate.