@article{120920aa4fd7490b8632ef304778f958,
title = "A mechanism for tunable autoinhibition in the structure of a human Ca 2+/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. PaperFlick:",
author = "Chao, {Luke H.} and Stratton, {Margaret M.} and Lee, {Il Hyung} and Rosenberg, {Oren S.} and Joshua Levitz and Mandell, {Daniel J.} and Tanja Kortemme and Groves, {Jay T.} and Howard Schulman and John Kuriyan",
note = "Funding Information: We thank Angus Nairn, Andr{\'e} Hoelz, Sebastian Deindl, Patricia Pellicena, Paul De Koninck, Jonathan Winger, and the members of the Kuriyan Lab for many discussions and insights. We thank Giulio Superi-Furga for bosutinib, David King for peptide synthesis and mass spectrometry, Alice Ting for the BirA vector, Tony Iavarone for mass spectrometry support, and Greg Hura for SAXS data collection. We thank Tiago Barros and Joel Guenther for review of the manuscript. We acknowledge Corie Ralston and the staff at Advanced Light Source beamlines 8.2.2 and 8.2.1 for assistance with data collection. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. ",
year = "2011",
month = sep,
day = "2",
doi = "10.1016/j.cell.2011.07.038",
language = "English",
volume = "146",
pages = "732--745",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "5",
}