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Title: Molecular mechanism of activation-triggered subunit exchange in Ca 2+ /calmodulin-dependent protein kinase II

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:
 [1] ;  [1] ;  [2] ;  [1] ;  [3] ;  [2] ;  [1] ;  [1] ;  [1] ;  [4] ; ORCiD logo [1] ; ORCiD logo [1] ;  [5] ;  [2] ; ORCiD logo [6]
  1. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, Howard Hughes Medical Inst.
  2. Univ. of California, Berkeley, CA (United States). Dept. of Chemistry
  3. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, Howard Hughes Medical Inst., Biophysics Graduate Group
  4. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology, Howard Hughes Medical Inst.
  5. Allosteros Therapeutics, Sunnyvale, CA (United States)
  6. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, Howard Hughes Medical Inst., Biophysics Graduate Group; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
Publication Date:
Grant/Contract Number:
AC02-05CH11231; R01GM101277; R01GM097357
Type:
Accepted Manuscript
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 5; Journal Issue: MARCH2016; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
National Institutes of Health (NIH); USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1379139