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Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
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Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
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Journal Article
Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
2020
Overview
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.
Publisher
eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
Subject
/ Biochemistry and Chemical Biology
/ Ca2+/calmodulin-dependent protein kinase II
/ Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors
/ Calcium-Calmodulin-Dependent Protein Kinase Type 2 - chemistry
/ Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
/ Humans
/ Isoforms
/ Kinases
/ Life Sciences & Biomedicine - Other Topics
/ Proteins
