title: A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme.
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.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors: Luke H
authors: LH
authors: Chao
authors: Margaret M
authors: MM
authors: Stratton
authors: Il-Hyung
authors: IH
authors: Lee
authors: Oren S
authors: OS
authors: Rosenberg
authors: Joshua
authors: J
authors: Levitz
authors: Daniel J
authors: DJ
authors: Mandell
authors: Tanja
authors: T
authors: Kortemme
authors: Jay T
authors: JT
authors: Groves
authors: Howard
authors: H
authors: Schulman
authors: John
authors: J
authors: Kuriyan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D020035:Holoenzymes; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2