Unknown

Dataset Information

0

Evolution of CASK into a Mg2+-sensitive kinase.


ABSTRACT: 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.

SUBMITTER: Mukherjee K 

PROVIDER: S-EPMC3286871 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Evolution of CASK into a Mg2+-sensitive kinase.

Mukherjee Konark K   Sharma Manu M   Jahn Reinhard R   Wahl Markus C MC   Südhof Thomas C TC  

Science signaling 20100427 119


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 kinas  ...[more]

Similar Datasets

| S-EPMC3640377 | biostudies-literature
| S-EPMC3447378 | biostudies-literature
| S-EPMC7201137 | biostudies-literature
| S-EPMC2862152 | biostudies-literature
| S-EPMC4227784 | biostudies-literature
| S-EPMC6391276 | biostudies-literature
| S-EPMC9500383 | biostudies-literature
| S-EPMC9651610 | biostudies-literature
2020-07-27 | GSE140572 | GEO
| S-EPMC2563093 | biostudies-literature