Flexible Linkers in CaMKII Control the Balance Between Activating and Inhibitory Autophosphorylation

Overview

Journal Elife

Specialty Biology

Date 2020 Mar 10

PMID 32149607

Citations 24

Authors

Moitrayee Bhattacharyya

Young Kwang Lee

Serena Muratcioglu

Baiyu Qiu

Priya Nyayapati

Howard Schulman

Jay T Groves

John Kuriyan

Affiliations

Soon will be listed here.

Abstract

The many variants of human Ca/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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