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

Mitrea, Diana M.; Cika, Jaclyn A.; Stanley, Christopher B.; Nourse, Amanda; Onuchic, Paulo L.; Banerjee, Priya R.; Phillips, Aaron H.; Park, Cheon-Gil; Deniz, Ashok A.; Kriwacki, Richard W.

doi:10.1038/s41467-018-03255-3

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

Journal Article · Mon Feb 26 00:00:00 EST 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-03255-3· OSTI ID:1427597

Mitrea, Diana M. ^[1]; Cika, Jaclyn A. ^[2];

^[3]; Nourse, Amanda ^[4]; Onuchic, Paulo L. ^[5];

^[5]; Phillips, Aaron H. ^[1]; Park, Cheon-Gil ^[1]; Deniz, Ashok A. ^[5];

^[6]

St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology
St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology; Univ. of Tennessee Health Sciences Center, Memphis, TN (United States). Integrative Biomedical Sciences Program
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biology and Biomedical Sciences Group. Biology and Soft Matter Division
St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology. Molecular Interaction Analysis Shared Resource
Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology; Univ. of Tennessee Health Sciences Center, Memphis, TN (United States). Dept. of Microbiology, Immunology and Biochemistry

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.

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Research Organization:: St. Jude Children’s Research Hospital, Memphis, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Scripps Research Inst., La Jolla, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); American Lebanese Syrian Associated Charities (ALSAC) (United States)

Grant/Contract Number:: AC05-00OR22725; P30 CA021765; P30 CA21765; 5RO1GM115634; RO1 GM066833

OSTI ID:: 1427597

Journal Information:: Nature Communications, Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 171 works

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59 BASIC BIOLOGICAL SCIENCES
intrinsically disordered proteins
molecular conformation
SAXS
single-molecule biophysics
supramolecular assembly

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

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