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Elife. 2016 Feb 2;5. pii: e13571. doi: 10.7554/eLife.13571.

Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA.

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, United States.
2
Integrative Biomedical Sciences Program, University of Tennessee Health Sciences Center, Memphis, United States.
3
Department of Immunology, St. Jude Children's Research Hospital, Memphis, United States.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States.
5
Biology and Biomedical Sciences Group, Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, United States.
6
Molecular Interactions Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, United States.
7
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, United States.

Abstract

The nucleolus is a membrane-less organelle formed through liquid-liquid phase separation of its components from the surrounding nucleoplasm. Here, we show that nucleophosmin (NPM1) integrates within the nucleolus via a multi-modal mechanism involving multivalent interactions with proteins containing arginine-rich linear motifs (R-motifs) and ribosomal RNA (rRNA). Importantly, these R-motifs are found in canonical nucleolar localization signals. Based on a novel combination of biophysical approaches, we propose a model for the molecular organization within liquid-like droplets formed by the N-terminal domain of NPM1 and R-motif peptides, thus providing insights into the structural organization of the nucleolus. We identify multivalency of acidic tracts and folded nucleic acid binding domains, mediated by N-terminal domain oligomerization, as structural features required for phase separation of NPM1 with other nucleolar components in vitro and for localization within mammalian nucleoli. We propose that one mechanism of nucleolar localization involves phase separation of proteins within the nucleolus.

KEYWORDS:

NPM1/B23/nucleophosmin; biophysics; human; intrinsically disordered proteins; nucleolar localization; nucleolus; phase separation; single molecule fluorescence; structural biology

PMID:
26836305
PMCID:
PMC4786410
DOI:
10.7554/eLife.13571
[Indexed for MEDLINE]
Free PMC Article

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