Please use this identifier to cite or link to this item:
Title: A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids
Authors: Kang, J.
Lim, L. 
Lu, Y. 
Song, J. 
Issue Date: 2019
Publisher: Public Library of Science
Citation: Kang, J., Lim, L., Lu, Y., Song, J. (2019). A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids. PLoS Biology 17 (6) : e3000327. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 526-residue Fused in sarcoma (FUS) undergoes liquid–liquid phase separation (LLPS) for its functions, which can further transit into pathological aggregation. ATP and nucleic acids, the universal cellular actors, were shown to modulate LLPS of FUS in a unique manner: enhancement and then dissolution. Currently, the driving force for LLPS of FUS is still under debate, while the mechanism for the modulation remains completely undefined. Here, by NMR and differential interference contrast (DIC) imaging, we characterized conformations,0020dynamics, and LLPS of FUS and its domains and subsequently their molecular interactions with oligonucleic acids, including one RNA and two single-stranded DNA (ssDNA) molecules, as well as ATP, Adenosine monophosphate (AMP), and adenosine. The results reveal 1) both a prion-like domain (PLD) rich in Tyr but absent of Arg/Lys and a C-terminal domain (CTD) abundant in Arg/Lys fail to phase separate. By contrast, the entire N-terminal domain (NTD) containing the PLD and an Arg-Gly (RG)-rich region efficiently phase separate, indicating that the ?-cation interaction is the major driving force; 2) despite manifesting distinctive NMR observations, ATP has been characterized to modulate LLPS by specific binding as oligonucleic acids but with much lower affinity. Our results together establish a unified mechanism in which the ?-cation interaction acts as the major driving force for LLPS of FUS and also serves as the target for modulation by ATP and oligonucleic acids through specific binding. This mechanism predicts that a myriad of proteins unrelated to RNA-binding proteins (RBPs) but with Arg/Lys-rich disordered regions could be modulated by ATP and nucleic acids, thus rationalizing the pathological association of Amyotrophic lateral sclerosis (ALS)-causing C9ORF72 dipeptides with any nucleic acids to manifest cytotoxicity. © 2019 Kang et al.
Source Title: PLoS Biology
ISSN: 1544-9173
DOI: 10.1371/journal.pbio.3000327
Rights: Attribution 4.0 International
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1371_journal_pbio_3000327.pdf4.94 MBAdobe PDF



Google ScholarTM



This item is licensed under a Creative Commons License Creative Commons