(C) Cartoon illustrating the GSK3 recognition motifs and location of residues affected in Aymé-Gripp syndrome. The GSK3 catalytic domain is depicted with its active site (red) and the site binding to the priming phosphorylated residue (green). To phosphorylate its substrates, GSK3 requires a priming phosphorylation on the substrate four amino acids downstream the residue to be phosphorylated. The serine/threonine residues sequentially targeted by GSK3 are shown (red). Upon phosphorylation, they act as priming residues (green) to allow the subsequent phosphorylation of the upstream Ser/Thr. The kinase phosphorylating Ser70 has not been characterized yet. The residues affected by Aymé-Gripp syndrome-causing mutations (Ser54, Thr58, Pro59, Ser62, and Pro69) are indicated in bold.