CAMK2A: Human calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha
PDB Code: 2VZ6
The protein kinase CAMK2α is mainly expressed in brain and forms oligomeric, ring like structures composed of 6-12 subunits. There are four isoforms present in mammalian cells (alpha, beta, gamma, and delta).
CAMK2α is a prominent kinase in the central nervous system which constitutes up to 1% of total brain protein. It plays an important function in long-term potentiation and neurotransmitter release, which has been demonstrated in numerous mouse models. CaMK2α is activated by NMDA receptors and is involved in phosporylation and trafficking of AMPA receptors, both of which are important steps in long term potentiation. Although no mutation of CAMK2α has been identified in the human dysregulated expression of CAMK2α has been described in several neurological disorders like Alzheimers’s disease, depression and bipolar illness. CAMK2α also controls the growth of human osteosarcoma by regulating cell cycle progression.
The overall organization of each of the four CAMK2 isoforms is similar: an N-terminal catalytic domain is followed by a regulatory domain that contains an autoinhibitory region with a calmodulin (CaM) binding site and a C-terminal association domain, through which the subunits interact to assemble into holoenzymes. A variable domain is located between the CaM-binding domain and the association domain.
CAMK2α is activated by a two step activation process: The first activation event involves the dissociation of the autoinhibitory regulatory segment. This process involves binding of Ca2+/CaM which leads to the exposure of a regulatory threonine residue. The now accessible threonine is phophorylated by a neighboring kinase domain within the oligomeric dodecameric assembly. Once activated phophorylation prevents rebinding of the regulatory segment to the kinase domain and binding of Ca2+/CaM. Thus, at high Ca2+/CaM concentration the phosphorylation at the regulatory threonine propagates rapidly through the holoenzyme resulting in active Ca2+/CaM-independent CAMK2α.
Here we present the structure of CAMK2α at 2.3 Å resolution in complex with the cell-permeable indirubin derivative IDR E804. This inhibitor blocks the Scr-Stat3 signaling pathway and displays anti-tumor properties and has been shown to be a potent, ATP-competitive inhibitor of the kinase activities of Src (IC50 = 430 nM), Cdk1/cyclin E (IC50 = 210 nM), Cdk2/cyclin A (IC50 = 540 nM), and Cdk1/cyclin B (IC50 = 1.65 µM).
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