Research ArticleStructural Biology

Evolution of CASK into a Mg2+-Sensitive Kinase

Sci. Signal.  27 Apr 2010:
Vol. 3, Issue 119, pp. ra33
DOI: 10.1126/scisignal.2000800

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A Changing Role for Mg2+?

Protein phosphorylation, perhaps the most familiar posttranslational modification, is mediated by a large family of protein kinases, which catalyze the transfer of a phosphate from ATP to a protein substrate. This process was long believed to require Mg2+ as an essential cofactor; thus, CASK [calcium/calmodulin (CaM)–activated serine-threonine kinase], which lacks an amino acid motif essential for Mg2+ binding, was initially thought to be a pseudokinase that was unable to phosphorylate substrates. Here, Mukherjee et al., who previously showed that CASK is an atypical kinase with catalytic activity that is inhibited by Mg2+, created a mutant form of CASK (CASK4M) that bound to and was stimulated by Mg2+. Structural and functional analyses of CASK4M enabled them to investigate the mechanisms through which Mg2+ facilitated catalytic activity, and phylogenetic analyses indicated that CASK evolved from a Mg2+-dependent kinase. CASK contains domains that enable it to bind to specific substrates, and the in vivo activity of CASK toward such a substrate was comparable to that of CASK4M. This, together with its appearance early in animal evolution, suggests that CASK’s loss of Mg2+-dependent catalytic activity—far from being detrimental—may have enabled the development of a novel mechanism through which it could be regulated by localized changes in divalent cation concentration.