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Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4466-71. doi: 10.1073/pnas.1321007111. Epub 2014 Mar 10.

Structural polymorphism in the N-terminal oligomerization domain of NPM1.

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  • 1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.

Abstract

Nucleophosmin (NPM1) is a multifunctional phospho-protein with critical roles in ribosome biogenesis, tumor suppression, and nucleolar stress response. Here we show that the N-terminal oligomerization domain of NPM1 (Npm-N) exhibits structural polymorphism by populating conformational states ranging from a highly ordered, folded pentamer to a highly disordered monomer. The monomer-pentamer equilibrium is modulated by posttranslational modification and protein binding. Phosphorylation drives the equilibrium in favor of monomeric forms, and this effect can be reversed by Npm-N binding to its interaction partners. We have identified a short, arginine-rich linear motif in NPM1 binding partners that mediates Npm-N oligomerization. We propose that the diverse functional repertoire associated with NPM1 is controlled through a regulated unfolding mechanism signaled through posttranslational modifications and intermolecular interactions.

KEYWORDS:

NMR; X-ray crystallography

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