Saturday, June 27, 2009

CaMK II (Ca2+/calmodulin-dependent protein kinase II)

Definition

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr protein kinase whose activity is regulated by Ca2+/calmodulin (CaM) complex1. It is predominant in the heart and plays an important role during excitation contraction coupling2.

Discovery

CaMKII was first purified from rat brain by gel filtration techniques while monitoring the activation of tryptophan hydrolase and phosphorylation of endogenous proteins3.

Classification

CaMK proteins belong to the kinase family4. CaMKII belongs to the CaMK subfamily of proteins which include the following members: CaMKI, CaMKII-alpha subunit, CaMKII-beta subunit, CaMKII-gamma subunit, CaMKII-delta subunit, CaMKIII and CaMKIV4.

Structural Characteristics

The four isoforms of CaMKII (a,b,g,d) are all encoded by different genes. a and b are predominant neural isoforms while g and d isoforms are expressed in many tissues including the heart. The CaMKII consists of an N-terminal catalytic domain followed by autoinhibitory, Ca2+/CaM binding and association domains5. Predicted CaMKII phosphorylation consensus motifs generally follow the form R-X-X-S/T. The autoinhibitory domain consists of a pseudosubstrate sequence that, under basal conditions, binds and constrains the catalytic domain5. The pseudosubstrate sequence is built around an activating "autophosphorylation" site at Thr286/287 (the precise numbering is isoform dependent). The enzyme assembles into dodecameric or tetradecomeric structures, with the catalytic domains sticking out, such that these may phosphorylate residues in an intersubunit fashion that increases their affinity to CaM complex5. In the absence of Ca2+/calmodulin, the autoinhibitory domain inhibits the catalytic domain6.

Mode of action

When intracellular Ca2+ increases, CaM binds up to four Ca2+ ions to form the Ca2+/CaM complex that binds to the regulatory domain of CaMKII thereby activating the enzyme with half maximal activation at Ca2+. After this Ca2+/CaM-dependent activation, CaMKII autophosphorylates Thr286/287 on the autoinhibitory segment resulting in a completely active enzyme that can maintain CaMK active even after Ca2+ has declined5. Activated CaMKII can phosphorylate various substrates5.

Functions

CaMKII modulates excitation-contraction coupling in the heart by regulating several Ca2+ handling proteins5. CaMKII has also been implicated in Ca2+ dependent axonal growth cone attraction, synaptic plasticity, learning and memory7. Excess CaMKII is associated with heart failure. Hence CaMK inhibitors are being designed in order to study their effect on reducing heart failure5.

References

1. Maier LS (2009). Role of CaMKII for signaling and regulation in the heart. Front Biosci., 14:486-96.

2. Wayman GA, Lee YS, Tokumitsu H, Silva A, Soderling TR (2008). Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron, 59(6), 914-31.

3. Yamauchi, T. and Fujisawa, H. (1980). Evidence for three distinct forms of calmodulin-dependent protein kinases from rat brain. FEBS Lett. 116, 141-144.

4. Steven KH and Tony H (1995). The eukaryotic protein kinase superfamily: kinase (catalytic) domam structure and classification. The Faseb Journal, 29, 576-96.

5. Couchonnal LF, Anderson ME (2008). The role of calmodulin kinase II in myocardial physiology and disease. Physiology (Bethesda).23:151-9.

6. Rosenberg OS, Deindl S, Sung RJ, Nairn AC, Kuriyan J (2005). Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell, 123, 849–860.

7. Lars SM and Donald MB (2007). Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovascular Research, 73(4), 631-640.

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