Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 3,282

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation

Patel, Avinash, Lee, Hyun O., Jawerth, Louise, Maharana, Shovamayee, Jahnel, Marcus, Hein, Marco Y., Stoynov, Stoyno, Mahamid, Julia, Saha, Shambaditya, Franzmann, Titus M., Pozniakovski, Andrej, Poser, Ina, Maghelli, Nicola, Royer, Loic A., Weigert, Martin, Myers, Eugene W., Grill, Stephan, Drechsel, David, Hyman, Anthony A., Alberti, Simon·2015·Cell
DOI 10.1016/j.cell.2015.07.047
Open this paper in CoChat — free account

Abstract

Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.

Overview

Integrity signals

Registry

Crossref · 10.1016/j.cell.2015.07.047

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 6 references

Research works printed but not linked: 54

  1. Aggarwal, 2013, Myelin membrane assembly is driven by a phase transition of myelin basic proteins into a cohesive protein meshwork, PLoS Biol., 11, e1001577, 10.1371/journal.pbio.1001577 · DOI
  2. Alberti, 2009, A systematic survey identifies prions and illuminates sequence features of prionogenic proteins, Cell, 137, 146, 10.1016/j.cell.2009.02.044 · DOI
  3. Banjade, 2014, Phase transitions of multivalent proteins can promote clustering of membrane receptors, eLife, 3, 3, 10.7554/eLife.04123 · DOI
  4. Behrndt, 2012, Forces driving epithelial spreading in zebrafish gastrulation, Science, 338, 257, 10.1126/science.1224143 · DOI
  5. Bosco, 2010, Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules, Hum. Mol. Genet., 19, 4160, 10.1093/hmg/ddq335 · DOI
  6. Brangwynne, 2009, Germline P granules are liquid droplets that localize by controlled dissolution/condensation, Science, 324, 1729, 10.1126/science.1172046 · DOI
  7. Brangwynne, 2011, Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes, Proc. Natl. Acad. Sci. USA, 108, 4334, 10.1073/pnas.1017150108 · DOI
  8. Decker, 2007, Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae, J. Cell Biol., 179, 437, 10.1083/jcb.200704147 · DOI
  9. Deng, 2014, The role of FUS gene variants in neurodegenerative diseases, Nat. Rev. Neurol., 10, 337, 10.1038/nrneurol.2014.78 · DOI
  10. Dumetz, 2008, Protein phase behavior in aqueous solutions: crystallization, liquid-liquid phase separation, gels, and aggregates, Biophys. J., 94, 570, 10.1529/biophysj.107.116152 · DOI
  11. Dutertre, 2014, DNA damage: RNA-binding proteins protect from near and far, Trends Biochem. Sci., 39, 141, 10.1016/j.tibs.2014.01.003 · DOI
  12. Galkin, 2000, Control of protein crystal nucleation around the metastable liquid-liquid phase boundary, Proc. Natl. Acad. Sci. USA, 97, 6277, 10.1073/pnas.110000497 · DOI
  13. Galkin, 2002, Liquid-liquid separation in solutions of normal and sickle cell hemoglobin, Proc. Natl. Acad. Sci. USA, 99, 8479, 10.1073/pnas.122055299 · DOI
  14. Gao, 2014, 3D live fluorescence imaging of cellular dynamics using Bessel beam plane illumination microscopy, Nat. Protoc., 9, 1083, 10.1038/nprot.2014.087 · DOI
  15. Gilks, 2004, Stress granule assembly is mediated by prion-like aggregation of TIA-1, Mol. Biol. Cell, 15, 5383, 10.1091/mbc.e04-08-0715 · DOI
  16. Gitler, 2011, RNA-binding proteins with prion-like domains in ALS and FTLD-U, Prion, 5, 179, 10.4161/pri.5.3.17230 · DOI
  17. Han, 2012, Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies, Cell, 149, 768, 10.1016/j.cell.2012.04.016 · DOI
  18. Hubstenberger, 2013, Translation repressors, an RNA helicase, and developmental cues control RNP phase transitions during early development, Dev. Cell, 27, 161, 10.1016/j.devcel.2013.09.024 · DOI
  19. Hyman, 2011, Beyond stereospecificity: liquids and mesoscale organization of cytoplasm, Dev. Cell, 21, 14, 10.1016/j.devcel.2011.06.013 · DOI
  20. Hyman, 2014, Liquid-liquid phase separation in biology, Annu. Rev. Cell Dev. Biol., 30, 39, 10.1146/annurev-cellbio-100913-013325 · DOI · Paper page
  21. Kedersha, 2005, Stress granules and processing bodies are dynamically linked sites of mRNP remodeling, J. Cell Biol., 169, 871, 10.1083/jcb.200502088 · DOI
  22. Kim, 2013, Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS, Nature, 495, 467, 10.1038/nature11922 · DOI
  23. King, 2012, The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease, Brain Res., 1462, 61, 10.1016/j.brainres.2012.01.016 · DOI
  24. Kwiatkowski, 2009, Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis, Science, 323, 1205, 10.1126/science.1166066 · DOI
  25. Kwon, 2013, Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains, Cell, 155, 1049, 10.1016/j.cell.2013.10.033 · DOI
  26. Kwon, 2014, Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells, Science, 345, 1139, 10.1126/science.1254917 · DOI
  27. Lee, 2013, Spatial organization of the cell cytoplasm by position-dependent phase separation, Phys. Rev. Lett., 111, 088101, 10.1103/PhysRevLett.111.088101 · DOI
  28. Li, 2012, Phase transitions in the assembly of multivalent signalling proteins, Nature, 483, 336, 10.1038/nature10879 · DOI
  29. Li, 2013, Stress granules as crucibles of ALS pathogenesis, J. Cell Biol., 201, 361, 10.1083/jcb.201302044 · DOI
  30. Lomakin, 2003, Liquid-solid transition in nuclei of protein crystals, Proc. Natl. Acad. Sci. USA, 100, 10254, 10.1073/pnas.1334069100 · DOI
  31. Malinovska, 2013, Protein disorder, prion propensities, and self-organizing macromolecular collectives, Biochim. Biophys. Acta, 1834, 918, 10.1016/j.bbapap.2013.01.003 · DOI
  32. Mastrocola, 2013, The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage, J. Biol. Chem., 288, 24731, 10.1074/jbc.M113.497974 · DOI
  33. Mayer, 2010, Anisotropies in cortical tension reveal the physical basis of polarizing cortical flows, Nature, 467, 617, 10.1038/nature09376 · DOI
  34. Nomura, 2014, Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis, J. Biol. Chem., 289, 1192, 10.1074/jbc.M113.516492 · DOI
  35. Planchon, 2011, Rapid three-dimensional isotropic imaging of living cells using Bessel beam plane illumination, Nat. Methods, 8, 417, 10.1038/nmeth.1586 · DOI
  36. Polymenidou, 2012, Misregulated RNA processing in amyotrophic lateral sclerosis, Brain Res., 1462, 3, 10.1016/j.brainres.2012.02.059 · DOI · Paper page
  37. Poser, 2008, BAC TransgeneOmics: a high-throughput method for exploration of protein function in mammals, Nat. Methods, 5, 409, 10.1038/nmeth.1199 · DOI
  38. Ramaswami, 2013, Altered ribostasis: RNA-protein granules in degenerative disorders, Cell, 154, 727, 10.1016/j.cell.2013.07.038 · DOI
  39. Rulten, 2014, PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage, Nucleic Acids Res., 42, 307, 10.1093/nar/gkt835 · DOI
  40. Schwartz, 2012, FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2, Genes Dev., 26, 2690, 10.1101/gad.204602.112 · DOI
  41. Serio, 2000, Nucleated conformational conversion and the replication of conformational information by a prion determinant, Science, 289, 1317, 10.1126/science.289.5483.1317 · DOI
  42. Shelkovnikova, 2014, Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms, Hum. Mol. Genet., 23, 5211, 10.1093/hmg/ddu243 · DOI
  43. Strzelecka, 2010, Coilin-dependent snRNP assembly is essential for zebrafish embryogenesis, Nat. Struct. Mol. Biol., 17, 403, 10.1038/nsmb.1783 · DOI
  44. Sun, 2011, Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS, PLoS Biol., 9, e1000614, 10.1371/journal.pbio.1000614 · DOI
  45. Toretsky, 2014, Assemblages: functional units formed by cellular phase separation, J. Cell Biol., 206, 579, 10.1083/jcb.201404124 · DOI
  46. Vance, 2009, Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6, Science, 323, 1208, 10.1126/science.1165942 · DOI
  47. Vekilov, 2004, Dense liquid precursor for the nucleation of ordered solid phases from solution, Cryst. Growth Des., 4, 671, 10.1021/cg049977w · DOI
  48. Vekilov, 2010, Phase transitions of folded proteins, Soft Matter, 6, 5254, 10.1039/c0sm00215a · DOI
  49. Wang, 2008, Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription, Nature, 454, 126, 10.1038/nature06992 · DOI
  50. Wang, 2013, Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons, Nat. Neurosci., 16, 1383, 10.1038/nn.3514 · DOI
  51. Weber, 2012, Getting RNA and protein in phase, Cell, 149, 1188, 10.1016/j.cell.2012.05.022 · DOI
  52. Wippich, 2013, Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling, Cell, 152, 791, 10.1016/j.cell.2013.01.033 · DOI
  53. Woulfe, 2010, FUS-immunoreactive intranuclear inclusions in neurodegenerative disease, Brain Pathol., 20, 589, 10.1111/j.1750-3639.2009.00337.x · DOI
  54. Yang, 2014, Self-assembled FUS binds active chromatin and regulates gene transcription, Proc. Natl. Acad. Sci. USA, 111, 17809, 10.1073/pnas.1414004111 · DOI

Cited by

Metadata

Authors
Patel, A., Lee, H. O., Jawerth, L., Maharana, S., Jahnel, M., Hein, M. Y., Stoynov, S., Mahamid, J., Saha, S., Franzmann, T. M., Pozniakovski, A., Poser, I., Maghelli, N., Royer, L. A., Weigert, M., Myers, E. W., Grill, S., Drechsel, D., Hyman, A. A., & Alberti, S.
Venue
Cell
Publisher
Elsevier BV
Published
2015-08
Volume
162
Issue
5
Pages
1066-1077
ISSN
0092-8674
DOI
10.1016/j.cell.2015.07.047
Cited by
3,282
References
6
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.