title: Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin-dependent protein kinase II.
abstract: Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Moitrayee
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Stratton
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Going
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: McSpadden
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.|Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Susa
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Elleman
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Yumeng Melody
authors.initials: YM
authors.lastname: Cao
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Nishant
authors.initials: N
authors.lastname: Pappireddi
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Pawel
authors.initials: P
authors.lastname: Burkhardt
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Christine L
authors.identifier: 0000-0002-2632-6418
authors.initials: CL
authors.lastname: Gee
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Tiago
authors.identifier: 0000-0002-9807-7625
authors.initials: T
authors.lastname: Barros
authors.affiliation: Allosteros Therapeutics, Sunnyvale, United States.
authors.forename: Howard
authors.initials: H
authors.lastname: Schulman
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Williams
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.|California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States.|Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.|Biophysics Graduate Group, University of California, Berkeley, Berkeley, United States.|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States.
authors.forename: John
authors.identifier: 0000-0002-4414-5477
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D055503:Protein Multimerization; D021122:Protein Subunits / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+/CaM stimulus; E. coli; N. vectensis; S. rosetta; biochemistry; biophysics; kinase activation; structural biology; structural transition; subunit exchange