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PDBsum entry 3mfs
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References listed in PDB file
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Key reference
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Title
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Evolution of cask into a mg2+-Sensitive kinase.
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Authors
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K.Mukherjee,
M.Sharma,
R.Jahn,
M.C.Wahl,
T.C.Südhof.
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Ref.
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Sci Signal, 2010,
3,
ra33.
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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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.
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