CAMK, also known as CaMK, is an abbreviation for enzymes in the Ca²⁺/calmodulin-dependent protein kinase class. CAMK is activated by increasing the concentration of intracellular calcium (Ca²⁺) and calmodulin. After activation, the enzyme transfers phosphate from ATP to serine or threonine residues defined in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and is therefore involved in the regulation of expression of response genes. CAMK is also used to regulate the cell life cycle (ie, programmed cell death), rearrangement of the cytoskeleton network, and mechanisms involved in biological learning and memory.

Calcium/calmodulin-dependent protein kinase type 1

Calcium/calmodulin-dependent protein kinase type 1 is an enzyme encoded by the CAMK1 gene in humans. Cal/calmodulin-dependent protein kinase I is expressed in many tissues and is part of the calmodulin-dependent protein kinase cascade. Calcium/calmodulin directly activates calcium/calmodulin-dependent protein kinase I by binding to the enzyme, and indirectly promotes phosphorylation and synergistic activation of the enzyme through calcium/calmodulin-dependent protein kinase I kinase.

Figure 1. Protein structure of CAMK1.

Crystal structure of calcium/calmodulin-dependent protein kinase 2

Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the Ca²⁺/calmodulin complex. CaMKII participates in many signal cascades and is considered an important medium for learning and memory. CaMKII is also necessary for Ca²⁺ homeostasis and myocardial cell reuptake, chloride ion transport in the epithelium, positive T cell selection, and CD8 T cell activation.

Figure 2. Crystal structure of calcium/calmodulin-dependent protein kinase.

Calcium and calmodulin dependence

The sensitivity of the CaMKII enzyme to calcium and calmodulin is controlled by variable and self-associated domains. This sensitivity level of CaMKII will also regulate different activation states of the enzyme. Initially, the enzyme is activated; however, since there is not enough calcium or calmodulin to bind to an adjacent subunit, autophosphorylation does not occur. With the accumulation of a large amount of calcium and calmodulin, autophosphorylation occurs, resulting in continuous activation of CaMKII enzyme for a short period of time. However, the threonine 286 residue was eventually dephosphorylated, causing CaMKII inactivation.

Figure 3. The structure of the kinase domain of CaMKII (gamma) rendered by pymol from PDB 2v7O, green sticks = nucleotide.

CAMKIIα

Calcium/calmodulin-dependent protein kinase type II subunit (CAMKIIα), also known as Ca²⁺/calmodulin-dependent protein kinase IIα, is a protein kinase encoded by the human CAMK2A gene. The product of the CAMK2A gene is an enzyme that belongs to the serine/threonine-specific protein kinase family and the Ca²⁺/calmodulin-dependent protein kinase II subfamily. Ca²⁺ ion signaling is essential for several aspects of glutamate synaptic plasticity. The enzyme consists of four different chains: α, β, γ, and δ. The alpha chain encoded by this gene is required for hippocampal long-term enhancement (LTP) and spatial learning. In addition to its calcium calmodulin (CaM) -dependent activity, the protein can also undergo autophosphorylation, resulting in CaM-independent activity. Two transcript variants encoding different isoforms have been identified for this gene.

Figure 4. Protein structure of CAMKIIα.

Some of pseudokinases that are related to the CAMK family include:

Tribbles-1

Tribbles-1 is one of three members of the Tribbles subfamily, which is part of the CAMK Ser/Thr protein kinase family of protein kinase superfamily. The Tribbles subfamily is one of the pseudokinases, which means that although the putative kinase region is expressed in its structure, it is non-catalytic. The Tribbles subfamily lacks a functional ATP-binding pocket, and therefore cannot phosphorylate its substrate; instead, the Tribbles protein functions as a scaffold protein that binds to its substrate to localize them to function.

Tribbles-2

Tribbles homolog 2 is an atypical protein kinase encoded by the TRIB2 gene in humans. TRIB2 is a pseudokinase member of the signal/scaffold protein (pseudoenzyme) class and has almost no residual catalytic output in vitro. Signals are known to transduce the typical MAPK pathway and regulate ubiquitination of substrates with important functions in the immune system. It is also associated with many diseases, especially in vertebrate leukemia models. Like TRIB1 and TRIB3, TRIB2 has recently been recognized as a potential allosteric drug target and is a regulator of putative cancer-related signals and survival through AKT pSer473 regulation.

Reference

1. Swulius MT; et al. Ca(2+)/calmodulin-dependent protein kinases. Cellular and Molecular Life Sciences. 2008, 65 (17): 2637-57.