Figure 4.
Two distinct inactive conformations of the CaMKII holoenzyme: compact and extended. (a) The only current holoenzyme crystal structure (in a compact conformation) with accurate kinase domain positioning (left; PDB1 3SOA) [31] was derived from a monomeric linker-less CaMKIIα with a partial association domain (right; PDB 3SOA) [31], together with the known structure of the association domain assembly [32, 44, 46]. (b) In a compact conformation, the kinase domains fold back to the association domains, leaving the CaM-binding regulatory domain inaccessible to stimulation (as depicted in the crystal structure in panel a) [31]. In an extended conformation, the kinase domains protrude further outward, making the regulatory domains accessible (compare to the model depicted in Fig. 1b). CaM-binding to the extended conformation may, in turn, also favor transition of neighboring subunits to this CaM-binding competent extended conformation [31]. (c) Small-angle X-ray scattering (SAXS) analysis indicates that the I321E mutation in a linker-less CaMKIIα that interferes with the interaction of the kinase domain with the association domain causes a transition from a compact (i) to an extended conformation (ii) [31]. This mutation reduces cooperativity of activation by CaM not only for linker-less but also for full-length CaMKIIα (wild type, iii), at least under molecular crowding conditions that mimic cellular protein concentrations [31]. In SAXS analysis (without molecular crowding) the major CaMKIIα isoform was found in the extended conformation [31]. All panels are adapted, with permission, from [31].