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.
Highlights
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr kinase that is important in neuronal signaling and cardiac function (Colbran et al, 1989a; Giese and Mizuno, 2013; Hook and Means, 2001; Kandel et al, 2014; Lisman and Raghavachari, 2015; Lisman et al, 2002; Luo and Anderson, 2013)
Biochemistry Biophysics and structural biology that crystal structures of the isolated hub domains of CaMKII from C. elegans and mammalian species show them to be assembled into both dodecamers (Rellos et al, 2010) and tetradecamers (Hoelz et al, 2003; Rosenberg et al, 2006)
Our results provide an understanding of how the structural integrity of CaMKII holoenzymes is altered by activation, thereby triggering subunit exchange
Summary
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr kinase that is important in neuronal signaling and cardiac function (Colbran et al, 1989a; Giese and Mizuno, 2013; Hook and Means, 2001; Kandel et al, 2014; Lisman and Raghavachari, 2015; Lisman et al, 2002; Luo and Anderson, 2013). CaMKII has a unique architecture, in which the catalytic domains are linked flexibly to a hub domain, called the association domain, which forms a dodecameric or tetradecameric assembly (see Figure 1A for a description of the domains of CaMKII) (Chao et al, 2011; Kanaseki et al, 1991; Kolb et al, 1998; Kolodziej et al, 2000; Morris and Torok, 2001; Rosenberg et al, 2006; Stratton et al, 2013; Woodgett et al, 1983) This organization, in which twelve or more kinase domains are maintained in close proximity, enables the highly cooperative activation of CaMKII by Ca2+/calmodulin (Ca2+/CaM) and the integration of calcium inputs (Bradshaw et al, 2003; Chao et al, 2010, 2011; De Koninck and Schulman, 1998)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
