CASK Phosphorylates Neurexins
Kinases, which phosphorylate other proteins to regulate their activity, are a major player in signal transduction, and as such, major drug development targets as well. Roughly 10 percent of kinases, though, have mutations that seem, at first blush, to prevent them from phosphorylating proteins for one reason or another, which has earned them the collective name pseudokinases and the assumption that their kinase domains are inactive.
But in the April 18, 2008 issue of Cell, researchers report that at least one such kinase is nevertheless able to activate itself by autophosphorylation, and then phosphorylate other proteins as well.
The kinase in question, CASK, has been an enigmatic protein in many ways, first author Konark Mukherjee told BioWorld Today. CASK knockout mice die at birth and have cleft palates, but it has been unclear why.
CASK has been considered a pseudokinase because it has mutations that prevent it from binding magnesium, which is normally required for a kinase to phosphorylate its target. But in the course of studies designed to find out more about its interactions with other proteins, Mukherjee and his colleagues - at the University of Texas Southwestern Medical Center, the University of Goettingen, Germany, and the Max-Planck-Institute for Biophysical Chemistry, also in Göttingen, Germany, and the European Molecular Biology Laboratory in Hamburg, Germany - found that CASK is nevertheless able to activate itself by autophosphorylation, and then phosphorylate other proteins as well.
Rather than binding magnesium, the CASK relies on another mechanism to phosphorylate proteins physical proximity. Magnesium functions as a catalyst for kinases. In its absence, phosphorylation can still occur, but its rate is much lower. CASK increases this rate by binding proteins near the binding site for ATP, which donates the phosphate group in the phosphorylation reaction.
In fact, Mukherjee said, magnesium's effect on CASK is the opposite of its usual effect on kinases; rather than being required for activity, magnesium - as well as calcium - inhibits the activity of CASK. And because magnesium levels increase during neural activity, this inhibition by magnesium leads Mukherjee and his team to conclude that the kinase domain is probably only functional in inactive neurons, though he said that data in support of this idea is currently still lacking.
Mukherjee stressed that CASK as a whole has multiple domains and so must have multiple functions. But the kinase function of CASK is only active during development, while synapses are being organized but before they are active.
In cell cultures experiments, Mukherjee and his colleagues found that when it is active, CASK phosphorylates so-called neurexins, a group of proteins that are themselves important for synaptic development. Mutations in neurexins - as well as in CASK itself - have been linked to the development of autism, blindness, and mental retardation.
Aside from their possible biomedical relevance, Mukherjee said that the study has several basic science implications. It challenges the current concept of pseudokinases; in their paper, Mukherjee and his colleagues write that such pseudokinases may turn out to be enzymatically active kinases with special properties.
The discoveries will also allow scientists to understand the role that magnesium plays in regular kinase function. Currently, the most common idea is that magnesium acts as a charge shield, during the transfer of phosphate groups, but in the absence of a kinase that is active without magnesium, this idea - and any other - has been difficult to test, Mukherjee said; studies with CASK will really shed light on what magnesium actually does in phosphotransfer.
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