CAMK2G - Kinase domain
CAMK2G - Kinase domain: Human calcium/calmodulin-dependent protein kinase (CaM kinase) II gamma, kinase domain
PDB Code: 2V7O
The protein kinase CAMK2γ is ubiquitously expressed and forms oligomeric, ring like structures composed of 6-12 subunits. There are four isoforms present in mammalian cells (alpha, beta, gamma, and delta).
CAMK2γ is one of the most important transducers of Ca2+ signals and has been linked to a multitude of regulatory pathways. For example, regulatory functions for CAMK2γ have been suggested in cardiomyocyte apoptosis, memory, influencing immature T cell lifespan and T cell memory function and modulation of TCR signalling strength. A scaffolding function for the assembly of a postsynaptic signalosome, a role as mediator of synaptic plasticity and in bipolar spindle formation, as well as regulation of osteoclastogenesis has also been proposed.
The overall organization of each of the four CAMK2γ 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. Most splice variant differences map to this region. CAMK2γ 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 CAMK2γ .
Surprisingly, the structure of the association domain of mouse CAMK2α revealed a stacked arrangement of two 7-fold symmetric rings which has been attributed to the lacking kinase domain in the complex. However this association behavior might be specific for the alpha isoform or splice variant used. Here we present the structure of the association domain of in CAMK2γ in its dodecameric association state as well as the structure of the kinase domain in complex with the ATP competitive inhibitor BIM9.
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