Editors' ChoiceKinases

Just When You Thought It Was Pseudo

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Science Signaling  22 Apr 2008:
Vol. 1, Issue 16, pp. ec138
DOI: 10.1126/stke.116ec138

Approximately 10% of all known kinases are thought to be catalytically inactive because they have modifications of conserved motifs in their kinase domains, leading to their being dubbed pseudokinases. The pseudokinase Ca2+/calmodulin (CaM)-activated serine-threonine kinase (CASK) has an altered DFG motif in its N-terminal CaM-kinase domain. This motif is important for the binding of Mg2+, which helps to coordinate the binding of ATP, the source of the phosphoryl group for the kinase. CASK binds to synaptic adhesion molecules, including neurexin, and deletion of CASK in mice leads to synaptic defects and perinatal death. Mukherjee et al. determined the crystal structure of the CaM-kinase domain of recombinant CASK and compared it with those of other kinases. The N- and C-terminal lobes of the CASK CaM-kinase domain in the absence of ATP were arranged in a similar fashion as those of other kinases when in their active states, indicating that CASK adopts a constitutively active conformation. In vitro experiments showed that a fluorescent ATP analog bound to recombinant CASK in the absence of coordinating Mg2+ and that the addition of Mg2+ inhibited this interaction. In vitro kinase assays showed that the CASK CaM-kinase domain exhibited autophosphorylation activity, that the kinetics of this phosphorylation were similar to those of true kinases, and that Mg2+ and other divalent cations inhibited this activity. Overexpression of wild-type CASK but not a catalytically inactive CASK mutant in rat hippocampal neurons resulted in increased phosphorylation of β-neurexin compared with that in control neurons. As Kannan and Taylor discuss in commentary, this study challenges the idea that pseudokinases act merely as inactive scaffold proteins and should stimulate reinvestigation of their potential catalytic activity.

K. Mukherjee, M. Sharma, H. Urlaub, G. P. Bourenkov, R. Jahn, T. C. Südhof, M. C. Wahl, CASK functions as a Mg2+-independent neurexin kinase. Cell 133, 328-339 (2008). [PubMed]

N. Kannan, S. S. Taylor, Rethinking pseudokinases. Cell 133, 204-205 (2008). [PubMed]

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