PDBsum entry 3mfs

Transferase

PDB id: 3mfs

Contents

Protein chain

303 a.a. *

Ligands

ANP

Waters ×199

* Residue conservation analysis

PDB id:

3mfs

Name:

Transferase

Title:

Cask-4m cam kinase domain, amppnp

Structure:

Peripheral plasma membrane protein cask. Chain: a. Fragment: cask-4m cam kinase domain, rersidues 1-337. Synonym: hcask, calcium/calmodulin-dependent serine protein kinase, protein lin-2 homolog. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cask, lin2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.221 R-free: 0.268

Authors:

M.C.Wahl,K.Mukherjee

Key ref:

K.Mukherjee et al. (2010). Evolution of CASK into a Mg2+-sensitive kinase. Sci Signal, 3, ra33. PubMed id: 20424264

Date:

03-Apr-10 Release date: 28-Apr-10

Protein chain

O14936  (CSKP_HUMAN) -  Peripheral plasma membrane protein CASK from Homo sapiens

Seq: 926 a.a.

Struc: 303 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Sci Signal 3:ra33 (2010)

PubMed id: 20424264

Evolution of CASK into a Mg2+-sensitive kinase.

K.Mukherjee, M.Sharma, R.Jahn, M.C.Wahl, T.C.Südhof.

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.