دورية أكاديمية
أعرض في EDS

A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids.

التفاصيل البيبلوغرافية
العنوان: A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids.
المؤلفون: Jian Kang, Liangzhong Lim, Yimei Lu, Jianxing Song
المصدر: PLoS Biology, Vol 17, Iss 6, p e3000327 (2019)
بيانات النشر: Public Library of Science (PLoS), 2019.
سنة النشر: 2019
المجموعة: LCC:Biology (General)
مصطلحات موضوعية: Biology (General), QH301-705.5
الوصف: 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, dynamics, 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 π-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 π-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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1544-9173
1545-7885
Relation: https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885
DOI: 10.1371/journal.pbio.3000327
URL الوصول: https://doaj.org/article/f6415b2bf0094630bf592e2651194a1f
رقم الأكسشن: edsdoj.f6415b2bf0094630bf592e2651194a1f
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:15449173
15457885
DOI:10.1371/journal.pbio.3000327