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Nat Commun. 2018 Feb 26;9(1):842. doi: 10.1038/s41467-018-03255-3.

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

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
2
Integrative Biomedical Sciences Program, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA.
3
Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY, 10016, USA.
4
Biology and Biomedical Sciences Group, Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN, 37830, USA.
5
Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
7
Department of Physics, University of Buffalo, Buffalo, NY, 14260, USA.
8
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. richard.kriwacki@stjude.org.
9
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA. richard.kriwacki@stjude.org.

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.

PMID:
29483575
PMCID:
PMC5827731
DOI:
10.1038/s41467-018-03255-3
[Indexed for MEDLINE]
Free PMC Article

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