Figure 3.

Model of conformational changes in the catalytic domain of MARK2. The model is based on the X-ray structure of MARK2 [PDB: 1Y8G] [24]. The catalytic loop (grey) is located deep in the cleft between the small and the large lobes of the kinase domain (blue). The ubiquitin-associated (UBA) domain (red) in the back is linked to the large lobe by a stretch that contains the common docking (CD) site (green). (A) In the inactive state, the catalytic loop (yellow; partly disordered and modeled here as dotted line) is folded back into the cleft and resides underneath the ATP-binding loop (P-loop). Both T208 and S212 point to the right and are accessible for kinases, for example, T208 to MARKK [17] and S212 to GSK3β [19]. (B) In the activated state, phosphorylation of the T208 (indicated by red sphere) results in a reorientation of the activation loop. It becomes folded out of the cleft and resides between helix C and helix F, stabilized by interactions of the pT208 to residues in helix C. S212 is now fixed by hydrogen bonds towards K177 and D175 in the catalytic loop (grey). The catalytic pocket opens up and allows entry of ATP (violet) and substrate (tau peptide, cyan), which aligns with the catalytic (grey) and the activation loop (yellow). (C) Phosphorylation of S212, or mutation to alanine or glutamate, disrupts the stabilizing interaction between the activation loop (yellow) and the catalytic loop (grey), resulting in an inactive kinase. Furthermore, it is likely that the phosphate of pS212 (indicated by a red sphere) will interfere with the correct alignment of the substrate within the catalytic cleft.

Timm et al. BMC Neuroscience 2008 9(Suppl 2):S9   doi:10.1186/1471-2202-9-S2-S9