Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation.

ELife
Moitrayee BhattacharyyaJohn Kuriyan

Abstract

The many variants of human Ca2+/calmodulin-dependent protein kinase II (CaMKII) differ in the lengths and sequences of disordered linkers connecting the kinase domains to the oligomeric hubs of the holoenzyme. CaMKII activity depends on the balance between activating and inhibitory autophosphorylation (on Thr 286 and Thr 305/306, respectively, in the human α isoform). Variation in the linkers could alter transphosphorylation rates within a holoenzyme and the balance of autophosphorylation outcomes. We show, using mammalian cell expression and a single-molecule assay, that the balance of autophosphorylation is flipped between CaMKII variants with longer and shorter linkers. For the principal isoforms in the brain, CaMKII-α, with a ~30 residue linker, readily acquires activating autophosphorylation, while CaMKII-β, with a ~200 residue linker, is biased towards inhibitory autophosphorylation. Our results show how the responsiveness of CaMKII holoenzymes to calcium signals can be tuned by varying the relative levels of isoforms with long and short linkers.

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Citations

Apr 29, 2020·The European Journal of Neuroscience·Roman Sloutsky, Margaret M Stratton
Aug 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mateusz Dyla, Magnus Kjaergaard
Feb 4, 2021·Nature Communications·Akihiro C E ShibataHideji Murakoshi
Mar 29, 2021·Brain Research Bulletin·Martina Proietti Onori, Geeske M van Woerden
Mar 30, 2021·Frontiers in Cell and Developmental Biology·Javier DuranMaarten M G van den Hoogenhof
Jul 17, 2021·Genome Research·Diego Javier ZeaElodie Laine
Aug 16, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Martin W BerchtoldJonas M la Cour

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