Science · 2018 · 1.2K citations · 45 references
Life SciencesBiochemistryMolecular BiologyNeurodegenerationRna BiologyStructural BiologyProtein CondensatesRna FoldingRna LocalizationRna StructureRna-binding ProteinsRna-protein InteractionsLiquid-liquid Phase SeparationMembraneless OrganellesMessenger Rna Binding ProteinsPhase Separation MechanismsPrion Protein ConformationPrion Protein Domain ArchitecturePrion-like DomainsProtein-rna Condensates
RNA and membraneless organelles form via liquid‑liquid phase separation, and prion‑like RNA‑binding proteins such as FUS and TDP‑43 are normally soluble in the nucleus but can aggregate in the cytoplasm, linking them to neurodegenerative disease. The study seeks to identify factors that prevent random fusion of cellular condensates. The authors employed the RNA‑binding protein Whi3 to probe how RNA influences condensate formation. They found that RNA secondary structure and local concentration dictate the biophysical properties of Whi3 condensates, with high nuclear RNA buffering phase separation and low cytoplasmic RNA promoting aggregation. See Maharana et al., Science (p.
RNA and membraneless organelles Membraneless compartments can form in cells through liquidliquid phase separation (see the Perspective by Polymenidou). But what prevents these cellular condensates from randomly fusing together? Using the RNA-binding protein (RBP) Whi3, Langdon et al. demonstrated that the secondary structure of different RNA components determines the distinct biophysical and biological properties of the two types of condensates that Whi3 forms. Several RBPs, such as FUS and TDP43, contain prion-like domains and are linked to neurodegenerative diseases. These RBPs are usually soluble in the nucleus but can form pathological aggregates in the cytoplasm. Maharana et al. showed that local RNA concentrations determine distinct phase separation behaviors in different subcellular locations. The higher RNA concentrations in the nucleus act as a buffer to prevent phase separation of RBPs; when mislocalized to the cytoplasm, lower RNA concentrations trigger aggregation. Science , this issue p. 922 , p. 918 ; see also p. 859
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Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Manuela Neumann, Deepak M. Sampathu, Linda K. Kwong et al. · Science · 2006 · 6.6K citations
Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
Caroline Vance, Boris Rogelj, Tibor Hortobágyi et al. · Science · 2009 · 2.6K citations · Full text
Life Sciences, Genetics, Neurology +17