Evolution of CASK into a Mg2+-sensitive kinase.

TitleEvolution of CASK into a Mg2+-sensitive kinase.
Publication TypeJournal Article
Year of Publication2010
AuthorsMukherjee K, Sharma M, Jahn R, Wahl MC, Südhof TC
JournalSci Signal
Date Published2010 Apr 27
KeywordsBiocatalysis, Cell Line, Evolution, Molecular, Humans, Magnesium, Models, Molecular, Phylogeny, Protein Conformation, Protein Kinases

All known protein kinases, except CASK [calcium/calmodulin (CaM)-activated serine-threonine kinase], require magnesium ions (Mg(2+)) to stimulate the transfer of a phosphate from adenosine 5'-triphosphate (ATP) to a protein substrate. The CaMK (calcium/calmodulin-dependent kinase) domain of CASK shows activity in the absence of Mg(2+); indeed, it is inhibited by divalent ions including Mg(2+). Here, we converted the Mg(2+)-inhibited wild-type CASK kinase (CASK(WT)) into a Mg(2+)-stimulated kinase (CASK(4M)) by substituting four residues within the ATP-binding pocket. Crystal structures of CASK(4M) with and without bound nucleotide and Mn(2+), together with kinetic analyses, demonstrated that Mg(2+) accelerates catalysis of CASK(4M) by stabilizing the transition state, enhancing the leaving group properties of adenosine 5'-diphosphate, and indirectly shifting the position of the gamma-phosphate of ATP. Phylogenetic analysis revealed that the four residues conferring Mg(2+)-mediated stimulation were substituted from CASK during early animal evolution, converting a primordial, Mg(2+)-coordinating form of CASK into a Mg(2+)-inhibited kinase. This emergence of Mg(2+) sensitivity (inhibition by Mg(2+)) conferred regulation of CASK activity by divalent cations, in parallel with the evolution of the animal nervous systems.

Alternate JournalSci Signal
PubMed ID20424264
PubMed Central IDPMC3286871
Grant ListR37 MH052804 / MH / NIMH NIH HHS / United States
R37 MH052804-08 / MH / NIMH NIH HHS / United States
R37 MH52804-08 / MH / NIMH NIH HHS / United States