Flipping ATP to AMPlify Kinase Functions

Abstract

Understanding protein kinase family members that lack key catalytic residues-or pseudokinases-is a major challenge in cell signaling. In this issue of Cell, Sreelatha et al. (2018) describe how one pseudokinase transfers adenosine monophosphate (AMP) rather than phosphate to protein substrates, revealing unexpected catalytic diversity for the kinase fold.

Figure 1.. ATP Binds to Kinase Domain Folds in Flipped Orientations for AMPylation and Phosphorylation

The structure of SelO (upper), from PDB entry 6EAC, is show in pale cyan and grey, with the kinase fold colored cyan and the SelO-specific components grey. In the lower panel, the structure of the insulin receptor kinase in its active conformation (PDB entry 1IR3) is shown in pale magenta. Bound ATP is shown for each protein, with the γ-phosphate colored red, the α- and β-phosphates orange, and the rest of the molecule black. As depicted with the magnified molecules at left, the ATP orientation is flipped by ~180° about a vertical axis between the two proteins. As a result, whereas the γ-phosphate (red) faces ‘out’ of the kinase active site to be appended to substrate (right), AMP instead faces out of the SelO active site for substrate AMPylation (top right).