CAMKK family

Some members of the CaM kinase family are substrates for other kinases that themselves depend on Ca²⁺/CaM. The Ca²⁺/CaM-dependent protein activators of CaMKI and CaMKIV were purified separately. It was soon discovered that these activators were the same molecule, now called calmodulin-dependent protein kinase kinase (CaMKK), which is the most upstream element of the CaM kinase cascade involving the three CaM kinases mentioned above. The exact benefits of having independent enzymes in a signal cascade activated by the same allosteric modulator (Ca²⁺/ CaM) are not fully understood, but the CaM kinase cascade is not the only example of such a system. One potential benefit of this arrangement is the dynamic proofreading effect. In this way, the diffusion-limited step of the coupling reaction ensures that downstream enzymes are not fully activated unless the duration of the Ca²⁺ signal is long enough that all Both can be combined with Ca²⁺/CaM and then find another. It would make sense to see how the CaM kinase cascade of enzymes regulate gene transcription events, which can cause long-term biological changes that can only be initiated through error-proofing mechanisms.

Isoforms of CaMKK

CaMKK has two isoforms, an alpha isoform of 505 amino acids and a slightly larger beta isoform of 587 amino acids. Each is expressed from a separate gene, and they are all expressed as monomers in the cell. CaMKK is highest expressed in brain tissue, but alpha isoforms are also expressed in the thymus and spleen. In the cell, CaMKK resides in the cytoplasm and nucleus, prepares to respond to changes in cytoplasm and nucleus in Ca²⁺ concentration, and acts on two known substrates in the CaM kinase cascade. The domain structures of the two CaMKK isoforms are similar to other CaM kinases, with catalytic, self-inhibitory and CaM binding domains, and their structures extend from the N-terminus to the C-terminus. Although the crystal structure of CaMKK has not been solved, it may be very similar to other CaM kinases that have very similar characteristics to PKA. Like all CaM-dependent kinases, CaMKK's self-inhibitory domain keeps it in an inactive state, which interacts with the catalytic domain to prevent kinase activity. Ca²⁺/CaM binding mitigates this inhibition by displacing the self-inhibitory domain and exposing an effective catalytic site. This leads to the activation of CaMKK and subsequent phosphorylation of its downstream substrates CaMKI and CaMKIV, an event necessary but insufficient for its activation.

CaMKI kinases

CaMKI is one of two downstream targets in the CaM kinase cascade, so its activation requires both Ca²⁺/CaM binding and subsequent phosphorylation by CaMKK. It is a monomeric kinase of about 42 kDa expressed by three genes encoding α, β, and γ subtypes, and is widely distributed in most mammalian cells. CaMKI is a cytoplasmic protein, and little is known about the extent of its protein substrate, it probably has multiple functions.

General characteristics of Ca²⁺/calmodulin-activated protein kinase (CaM kinase)

The members of the CaM kinase family are all classified as Ser/Thr kinases, and their substrate P sites (target sites for phosphorylation) all contain Ser or Thr. As the name suggests, activation initially depends on Ca²⁺/CaM binding, but it is clear that some of them can become independent of Ca²⁺/CaM after activation or require other modifiers for other modifications (ie, phosphorylation). To achieve full activation. These regulatory differences allow relatively small families of proteins to display such excellent control over many different cellular functions. The overall domain of CaM kinase is very similar to the structure of PKA, one of which is a bilobal catalytic domain followed by a self-inhibition domain and a CaM binding domain. The self-suppression domain and the CaM binding domain overlap slightly, and the Ca²⁺/CaM binding regulates the function of the self-suppression domain. At basic Ca²⁺ levels, CaM kinases remain dormant through an autoinhibitory mechanism that involves regulatory domains downstream of the catalytic domain. Current data indicate that CaM kinase uses both strategies, sometimes even a combination of the two. Regardless of the self-inhibition mechanism, as the intracellular Ca²⁺ concentration increases (either by opening the receptor/ion channel or releasing from the intracellular storage), CaM will be saturated with four Ca²⁺ ions and undergo a conformational change, making Binding to a target site on CaM^-.

Reference:

1. Swulius M T; et al. Ca²⁺/Calmodulin-dependent Protein Kinases. Cellular and Molecular Life Sciences, 2008, 65(17):2637-2657.