Rethinking pseudokinases

Abstract

Pseudokinases lack conservation of one or more of the catalytic residues in the kinase core and as a consequence are typically thought to be catalytically inactive. New work by Mukherjee et al. (2008) challenges this assumption. They show that the pseudokinase domain of CASK (Ca2+/calmodulin activated serine-threonine kinase) adopts an active conformation and displays catalytic activity in vivo.

Figure 1.. Catalytic Versatility of the Protein Kinase Core

(Left) The active site of protein kinase A (PKA) is shown in a conformation that resembles a transition state (Madhusudan et al., 2002). The γ phosphate is trapped between the glycine-rich loop and Lys168 in the catalytic loop. The two Mg²⁺ ions are anchored by Asn171 in the catalytic loop and Asp185 in the DFG motif. (Right) The active site of CASK is shown bound to the ATP analog AMP-PNP; only the α phosphate is visible. Lys72 is conserved to anchor the α /β phosphates and the catalytic site (Lys168, Asp166) is poised to accept a substrate hydroxyl moiety. The critical backbone amide of Ser53 in PKA is replaced in CASK with a Pro, which provides a rigid cap but not a hydrogen bond. A histidine residue in the catalytic loop points toward the phosphates and can help to neutralize the charge in the ATP.