Ca2+/calmodulin-dependent protein kinase-II (CaMKII)
Caenorhabditis elegans (nematode)
Protein kinase is an enzyme which phosphorylates many proteins and the phosphorylated proteins change their own properties, for example enzymatic activities, intracellular localization and binding affinity. Ca2+/calmodulin-dependent protein kinase (CaMK) is a protein kinase which is activated by Ca2+/CaM complex and CaMKII which is a major CaMK in brain regulates secretion of neurotransmitters, activation or inactivation of transcription factors, metabolism of glycogen and so on.
CaMKII contains three domains, an N-terminal kinase domain, a regulatory segment and an association domain and forms a dodecametric holoenzyme. CaMKII has the unique property to retain a memory of prior activation by Ca2+/CaM because of a two step activation processes. In the first step, Ca2+/CaM removes the autoinhibitory regulatory segment located C terminal to the kinase domain. This releases the catalytic activity of the enzyme and makes accessible a threonine residue in the regulatory segment. The second step is the phosphorylation of the threonine by another kinase domain within the holoenzyme. Phosphorylation of the threonine residue keeps CaMKII active in the absence of Ca2+/CaM by preventing the rebinding of the regulatory segment to the kinase domain. Therefore, if the Ca2+ concentration is high, phosphorylation of a threonine residue in the regulatory segment will spread rapidly through the holoenzyme, leading to the onset of Ca2+/CaM-independent activity, while if the Ca2+ concentration is low the threonine residue is dephosphorylated before activation can proceed.
Rosenberg et al. reported the crystal structure of dimeric CaMKII and suggested that six CaMKII dimers form a 6-fold symmetric ring, which results in a dodecametric holoenzyme. This model nicely explains the transphosphorylation mechanism preventing improper phosphorylation. The regulatory segments of CaMKII form a dimeric coiled-coil structure. When CaMKII is inactive, the threonine residue in the regulatory segment is buried in the channel formed in the kinase domain so the threonine is protected against phosphorylation. Even if the threonine residue is spontaneously released from the channel, the threonine residue remains unphosphorylated because the coiled-coil strut keeps two active sites away from either of the threonine residue. Likewise, spontaneous disruption of the coiled-coil interaction still has the regulatory segment bound to the kinase domain. Therefore, the coiled-coil strut of the regulatory segment plays the key role in the autoinhibitory mechanism of CaMKII.
Protein Data Bank (PDB)
author: Daisuke Ino