Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation

Diana M. Mitrea, Jaclyn A. Cika, Christopher B. Stanley, Amanda Nourse, Paulo L. Onuchic, Priya R. Banerjee, Aaron H. Phillips, Cheon-Gil Park, Ashok A. Deniz and Richard W. Kriwacki ()
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Diana M. Mitrea: St. Jude Children’s Research Hospital
Jaclyn A. Cika: St. Jude Children’s Research Hospital
Christopher B. Stanley: Biology and Biomedical Sciences Group, Biology and Soft Matter Division, Oak Ridge National Laboratory
Amanda Nourse: St. Jude Children’s Research Hospital
Paulo L. Onuchic: The Scripps Research Institute
Priya R. Banerjee: The Scripps Research Institute
Aaron H. Phillips: St. Jude Children’s Research Hospital
Cheon-Gil Park: St. Jude Children’s Research Hospital
Ashok A. Deniz: The Scripps Research Institute
Richard W. Kriwacki: St. Jude Children’s Research Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Nucleophosmin (NPM1) is an abundant, oligomeric protein in the granular component of the nucleolus with roles in ribosome biogenesis. Pentameric NPM1 undergoes liquid–liquid phase separation (LLPS) via heterotypic interactions with nucleolar components, including ribosomal RNA (rRNA) and proteins which display multivalent arginine-rich linear motifs (R-motifs), and is integral to the liquid-like nucleolar matrix. Here we show that NPM1 can also undergo LLPS via homotypic interactions between its polyampholytic intrinsically disordered regions, a mechanism that opposes LLPS via heterotypic interactions. Using a combination of biophysical techniques, including confocal microscopy, SAXS, analytical ultracentrifugation, and single-molecule fluorescence, we describe how conformational changes within NPM1 control valency and switching between the different LLPS mechanisms. We propose that this newly discovered interplay between multiple LLPS mechanisms may influence the direction of vectorial pre-ribosomal particle assembly within, and exit from the nucleolus as part of the ribosome biogenesis process.

Date: 2018
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DOI: 10.1038/s41467-018-03255-3

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