SCIENCE SIGNALING

Just When You Thought It Was Pseudo...

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Science  02 May 2008:
Vol. 320, Issue 5876, pp. 587
DOI: 10.1126/science.320.5876.587c

Approximately 10% of the known protein kinases are thought to be catalytically inactive, and therefore dubbed pseudokinases, because they lack one or more conserved motifs in their active sites. The pseudokinase Ca2+/calmodulin (CaM)-activated serine- threonine kinase (CASK) has an altered DFG motif, which would normally bind a Mg2+ ion that coordinates the phosphoryl group to be transferred from ATP onto the substrate. CASK is known to bind to synaptic adhesion molecules, including neurexin, and CASK-deficient mice exhibit synaptic defects and perinatal death. Mukherjee et al. determined the structure of the CaM-kinase domain of CASK and found that it resembles a constitutively active kinase. They also show that a fluorescent ATP analog bound to recombinant CASK in the absence of Mg2+ and that adding Mg2+ inhibited this interaction. In vitro assays revealed that the CASK CaM-kinase domain exhibited autophosphorylation activity and that Mg2+ and other divalent cations inhibited this activity. Finally, overexpression of wild-type CASK in rat hippocampal neurons resulted in increased phosphorylation of neurexin, challenging the idea that pseudokinases act merely as inactive scaffold proteins. — JFF

Cell 133, 328 (2008).

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