Research ArticleBiochemistry

Tandem phosphorylation within an intrinsically disordered region regulates ACTN4 function

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Science Signaling  26 May 2015:
Vol. 8, Issue 378, pp. ra51
DOI: 10.1126/scisignal.aaa1977

Flipping the phosphorylation switch

How does phosphorylation of a protein at one site regulate phosphorylation of a second site? Travers et al. identified distinct roles for tandem phosphorylation sites in an intrinsically disordered region of α-actinin-4 (ACTN4). Molecular dynamics simulations, validated by experimental observations, indicated that phosphorylation on Tyr4 increased the accessibility of Tyr31 and thus phosphorylation of this site, which reduced ACTN4 binding to actin. Thus, the first site functioned as a switch that enabled phosphorylation at the second site, which controlled binding to actin. Tandem-site phosphorylation may be a mechanism by which spatiotemporal regulation of protein function evolved. The kinase for the first site may only be present or active at restricted locations or times, whereas the kinase for the second site may be constitutively active or ubiquitous, may have a loose consensus motif, or may be the same as the kinase for the first site, but has different kinetics for the second site.

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