A mechanism for tunable autoinhibition in the structure of a human Ca 2+/calmodulin-dependent kinase II holoenzyme Academic Article uri icon

Overview

MeSH Major

  • Calcium-Calmodulin-Dependent Protein Kinase Type 2

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.

publication date

  • September 2, 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3184253

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2011.07.038

PubMed ID

  • 21884935

Additional Document Info

start page

  • 732

end page

  • 45

volume

  • 146

number

  • 5