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A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme |
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| Authors: | Chao Luke H Stratton Margaret M Lee Il-Hyung Rosenberg Oren S Levitz Joshua Mandell Daniel J Kortemme Tanja Groves Jay T Schulman Howard Kuriyan John |
| Affiliation: | 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA 2 Department of Chemistry, University of California, Berkeley, CA 94720, USA 3 California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA 94720, USA 4 Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA 5 Biophysics Graduate Group, University of California, Berkeley, CA 94720, USA 6 California Institute for Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, CA 94143, USA 7 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94143, USA 8 Allosteros Therapeutics, Sunnyvale, CA 94089-1202, USA 9 Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA 10 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA |
| Abstract: | Calcium/calmodulin-dependent kinase II (CaMKII) forms a highly conserved dodecameric assembly that is sensitive to the frequency of calcium pulse trains. Neither the structure of the dodecameric assembly nor how it regulates CaMKII are known. We present the crystal structure of an autoinhibited full-length human CaMKII holoenzyme, revealing an unexpected compact arrangement of kinase domains docked against a central hub, with the calmodulin-binding sites completely inaccessible. We show that this compact docking is important for the autoinhibition of the kinase domains and for setting the calcium response of the holoenzyme. Comparison of CaMKII isoforms, which differ in the length of the linker between the kinase domain and the hub, demonstrates that these interactions can be strengthened or weakened by changes in linker length. This equilibrium between autoinhibited states provides a simple mechanism for tuning the calcium response without changes in either the hub or the kinase domains. |
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