Asymmetric Modulation of Protein Order–Disorder Transitions by Phosphorylation and Partner Binding. Issue 5 (17th December 2015)

• Record Type: Journal Article
• Authors: Banerjee, Priya R.; Mitrea, Diana M.; Kriwacki, Richard W.; Deniz, Ashok A.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 5(2016)
• Page Start: 1675
• Page End: 1679
• Publication Date: 2015-12-17
• Subjects: conformational landscape -- coupled folding and binding -- kinetics -- protein folding -- single-molecule FRET; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201507728
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: As for many intrinsically disordered proteins, order–disorder transitions in the N‐terminal oligomerization domain of the multifunctional nucleolar protein nucleophosmin (Npm‐N) are central to its function, with phosphorylation and partner binding acting as regulatory switches. However, the mechanism of this transition and its regulation remain poorly understood. In this study, single‐molecule and ensemble experiments revealed pathways with alternative sequences of folding and assembly steps for Npm‐N. Pathways could be switched by altering the ionic strength. Phosphorylation resulted in pathway‐specific effects, and decoupled folding and assembly steps to facilitate disorder. Conversely, binding to a physiological partner locked Npm‐N in ordered pentamers and counteracted the effects of phosphorylation. The mechanistic plasticity found in the Npm‐N order–disorder transition enabled a complex interplay of phosphorylation and partner‐binding steps to modulate its folding landscape. Abstract : A plastic landscape was found to facilitate the functional shape shifting of an oncogenic protein. Alternative folding–assembly pathways of this conditionally disordered protein (see picture) were revealed by single‐molecule and ensemble experiments. Posttranslational modification and partner binding had differential effects on individual steps and were able to counteract each other.