title: Asymmetric Modulation of Protein Order-Disorder Transitions by Phosphorylation and Partner Binding.
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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92307, USA.
authors.forename: Priya R
authors.initials: PR
authors.lastname: Banerjee
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Mitrea
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. richard.kriwacki@stjude.org.|Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA. richard.kriwacki@stjude.org.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92307, USA. deniz@scripps.edu.
authors.forename: Ashok A
authors.initials: AA
authors.lastname: Deniz
mesh_terms: D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins
keywords: conformational landscape; coupled folding and binding; kinetics; protein folding; single-molecule FRET