Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation

Abstract

Structural and biophysical studies reveal how CaMKII kinases, which are important for cellular learning and memory, are switched on by binding of Ca2+/calmodulin.

Characterization of a Central Ca2+/Calmodulin-dependent Protein Kinase IIα/β Binding Domain in Densin That Selectively Modulates Glutamate Receptor Subunit Phosphorylation

“…6A and in supplemental Fig. 1; corresponding to the CN17a peptide described in Vest et al (27)) interact with a series of binding pockets on the catalytic domain that can also be partially occupied by the regulatory domain in autoinhibited CaMKII (45,46) and that have been collectively termed the T-site (27). Consistent with this structure, potent inhibition by N-tide is highly dependent on N-terminal Lys-43-Arg-Pro residues (27); however, these residues are not conserved in densin-IN (Leu-799 -Leu-Ser).…”

Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein

“…The optimal spectral dispersion was achieved at 303 K, and this temperature was selected from a series of HSQC spectra recorded in the 277-320 K range (for both the free and complexed peptide). 1 H chemical shifts were referenced to the internal 4,4-dimethyl-4-silapentane-1-sulfonic acid standard, whereas 15 N chemical shifts were referenced indirectly via the gyromagnetic ratios. Both samples had the following compositions: ϳ0.9 mM 15 Nlabeled peptide, 20 mM MES buffer, pH 6.00, 20 mM NaCl, 3 mM NaN 3 , 2 mM TCEP, 5 mM CaCl 2 and 10% D 2 O. S100B concentration was ϳ2 mM in the complex.…”

“…The small tail in the P(r) function up to 6.5 nm can be an effect of the fuzziness of the intermediate and flanking part of the RSK1 peptide. E, overlay of the HSQC spectra of the free (red) and S100B complexed (blue) 15 N-labeled RSK1(683-735) peptide. Partial assignment of the free peptide is shown.…”

“…These kinases have a regulatory C-terminal extension, and in the inactive form the first segment of this tail forms a helical inhibitory helix that blocks substrate or cofactor binding, whereas the second segment is disordered. Upon Ca 2ϩ binding, calmodulin (CaM) opens up and binds to the unstructured tail and to the terminal part of the inhibitory helix (15). This interaction remodels the inhibitory segment and brings about an active kinase state (Fig.…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…[67][68][69][70] Ca 2C /CaM binding to the regulatory domain causes a conformational change that removes the autoinhibitory pseudosubstrate segment from the active site, which allows for ATP binding and also exposes T286 of the autoinhibitory pseudo-substrate segment for phosphorylation. 69,[71][72][73][74][75] This phosphorylation sterically prevents the inhibitory segment from returning to the active site once Ca 2C /CaM has dissociated, resulting in continued activation independent of calcium. 75,76 CaMKII subunits undergo cis-phosphorylation; pairing of subunit's catalytic domains allows for phosphorylation in trans, but this only occurs if both subunits are activated through Ca 2C /CaM binding.…”