Skip to content

Research at St Andrews

FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions

Research output: Contribution to journalArticlepeer-review

Author(s)

Seema Qamar, GuoZhen Wang, Suzanne J Randle, Francesco Simone Ruggeri, Juan A Varela, Julie Qiaojin Lin, Emma C Phillips, Akinori Miyashita, Declan Williams, Florian Ströhl, William Meadows, Rodylyn Ferry, Victoria J Dardov, Gian G Tartaglia, Lindsay A Farrer, Gabriele S Kaminski Schierle, Clemens F Kaminski, Christine E Holt, Paul E Fraser, Gerold Schmitt-Ulms & 4 more David Klenerman, Tuomas Knowles, Michele Vendruscolo, Peter St George-Hyslop

School/Research organisations

Abstract

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.

Close

Details

Original languageEnglish
Article numbere15
Pages (from-to)720-734
JournalCell
Volume173
Issue number3
DOIs
Publication statusPublished - 19 Apr 2018

    Research areas

  • Phase separation, Neuronal ribonucleoprotein granule, Synaptic new protein synthesis, Membraneless organelle, Cation-π, arginine methylation, Citrullination, Frontotemporal dementia, AFM-IR, Phase-sensitive fluorescent dyes

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. ThX-a next-generation probe for the early detection of amyloid aggregates

    Needham, L. M., Weber, J., Varela, J. A., Fyfe, J. W. B., Do, D. T., Xu, C. K., Tutton, L., Cliffe, R., Keenlyside, B., Klenerman, D., Dobson, C. M., Hunter, C. A., Müller, K. H., O'Holleran, K., Bohndiek, S. E., Snaddon, T. N. & Lee, S. F., 14 May 2020, In: Chemical Science. 11, 18, p. 4578-4583 6 p.

    Research output: Contribution to journalArticlepeer-review

  2. Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

    De, S., Wirthensohn, D. C., Flagmeier, P., Hughes, C., Aprile, F. A., Ruggeri, F. S., Whiten, D. R., Emin, D., Xia, Z., Varela, J. A., Sormanni, P., Kundel, F., Knowles, T. P. J., Dobson, C. M., Bryant, C., Vendruscolo, M. & Klenerman, D., 4 Apr 2019, In: Nature Communications. 10, 11 p., 1541.

    Research output: Contribution to journalArticlepeer-review

  3. Optical structural analysis of individual α-synuclein oligomers

    Varela, J. A., Rodrigues, M., De, S., Flagmeier, P., Gandhi, S., Dobson, C. M., Klenerman, D. & Lee, S. F., 23 Apr 2018, In: Angewandte Chemie International Edition. 57, 18, p. 4886-4890 5 p.

    Research output: Contribution to journalArticlepeer-review

  4. Comparative Analysis of Photoluminescence and Upconversion Emission from Individual Carbon Nanotubes for Bioimaging Applications

    Danne, N., Godin, A. G., Gao, Z., Varela, J. A., Groc, L., Lounis, B. & Cognet, L., 21 Feb 2018, In: ACS Photonics. 5, 2, p. 359-364 11 p.

    Research output: Contribution to journalArticlepeer-review

  5. Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

    Godin, A. G., Varela, J. A., Gao, Z., Danné, N., Dupuis, J. P., Lounis, B., Groc, L. & Cognet, L., Mar 2017, In: Nature Nanotechnology. 12, 3, p. 238-243 6 p.

    Research output: Contribution to journalArticlepeer-review

Related by journal

  1. Bacteria SAVED from viruses

    White, M. F., 9 Jul 2020, In: Cell. 182, 1, p. 5-6 2 p.

    Research output: Contribution to journalArticlepeer-review

  2. Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing

    Rojas, F., Silvester, E., Young, J., Milne, R., Tettey, M., Houston, D. R., Walkinshaw, M. D., Pérez-Pi, I., Auer, M., Denton, H., Smith, T. K., Thompson, J. & Matthews, K. R., 10 Jan 2019, In: Cell. 176, 1-2, p. 306-317 12 p., e16.

    Research output: Contribution to journalArticlepeer-review

  3. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal

    Mitchell, T. J., Turajlic, S., Rowan, A., Nicol, D., Farmery, J. H. R., O’Brien, T., Martincorena, I., Tarpey, P., Angelopoulos, N., Yates, L. R., Butler, A. P., Raine, K., Stewart, G. D., Challacombe, B., Fernando, A., Lopez, J. I., Hazell, S., Chandra, A., Chowdhury, S., Rudman, S. & 27 others, Soultati, A., Stamp, G., Fotiadis, N., Pickering, L., Au, L., Spain, L., Lynch, J., Stares, M., Teague, J., Maura, F., Wedge, D. C., Horswell, S., Chambers, T., Litchfield, K., Xu, H., Stewart, A., Elaidi, R., Oudard, S., McGranahan, N., Csabai, I., Gore, M., Futreal, P. A., Larkin, J., Lynch, A. G., Szallasi, Z., Swanton, C. & Campbell, P. J., 19 Apr 2018, In: Cell. 173, 3, p. 611-623 13 p., e17.

    Research output: Contribution to journalArticlepeer-review

  4. Cryo-EM structure of a relaxase reveals the molecular basis of DNA unwinding during bacterial conjugation

    Ilangovan, A., Kay, C. W. M., Roier, S., El Mkami, H., Salvadori, E., Zechner, E. L., Zanetti, G. & Waksman, G., 4 May 2017, In: Cell. 169, 4, p. 708-721 27 p., e12.

    Research output: Contribution to journalArticlepeer-review

ID: 256889174

Top