Pseudokinase is active after all

Don't judge a book—or a kinase—by its cover, based on new findings from Konark Mukherjee, Thomas Südhof (University of Texas Southwestern Medical Center, Dallas, TX), Markus Wahl (Georg-August-University, Göttingen, Germany), and colleagues. The group shows that a kinase predicted to be inactive has plenty of phosphorylation power.

This not-so-disabled kinase is CASK. CASK lacks the residues needed to coordinate magnesium, which was thought to be required to transfer phosphates. But the new findings suggest that CASK works without magnesium.

The group's new crystal structure of CASK adopted a conformation that is characteristic of constitutively active kinases. And it contained a pocket that looks like it should bind very well to ATP. “It would be weird,” says Südhof “for CASK to bind ATP and have an active conformation but be inactive.” The group thus thoroughly tested its kinase abilities.

Even in the absence of magnesium, CASK phosphorylated one of its known binding partners, a synaptic adhesion molecule called neurexin-1. The biological outcome of the modification is not known. CASK probably has several other substrates, as it is widely expressed and contains a protein-interacting scaffolding domain.

Several pseudokinases similarly lack magnesium coordination centers. At least some of these proteins might have previously overlooked phosphorlyation skills.