3MFT

CASK-4M CaM Kinase Domain, Mn2+

Summary for 3MFT

• Entry DOI: 10.2210/pdb3mft/pdb
• Related: 3C0G 3C0H 3C0I 3MFR 3MFS 3MFU
• Descriptor: Peripheral plasma membrane protein CASK (2 entities in total)
• Functional Keywords: catalytic mechanism, kinase catalysis, mg2+-mediated phosphate transfer, protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): O14936
• Total number of polymer chains: 1
• Total formula weight: 39291.05

Authors

Wahl, M.C.,Mukherjee, K. (deposition date: 2010-04-03, release date: 2010-04-28, Last modification date: 2023-09-06)

Primary citation

Mukherjee, K.,Sharma, M.,Jahn, R.,Wahl, M.C.,Sudhof, T.C.
Evolution of CASK into a Mg2+-sensitive kinase.
Sci.Signal., 3:ra33-ra33, 2010

PubMed 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.

PubMed: 20424264
DOI: 10.1126/scisignal.2000800

Experimental method

X-RAY DIFFRACTION (2.2 Å)