Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity
| Autor: | Lin Guo, Nathalie Wilmans, Wendy Scheveneels, Frederic Rousseau, Ludo Van Den Bosch, Nicole Hersmus, Jolien Steyaert, Steven Boeynaems, Masato Kato, Patrick Callaerts, Wanda Haeck, Philip Van Damme, James Shorter, Elke Bogaert, Thomas R. Caulfield, Joost Schymkowitz, Wim Robberecht |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
amyotrophic lateral sclerosis RNA-binding protein Protein aggregation AMYOTROPHIC-LATERAL-SCLEROSIS Medicine and Health Sciences Drosophila Proteins ARGININE METHYLATION Amyotrophic lateral sclerosis lcsh:QH301-705.5 Motor Neurons biology Frontotemporal lobar degeneration 3. Good health Cell biology Drosophila melanogaster frontotemporal lobar degeneration Life Sciences & Biomedicine Drosophila Protein RNA-BINDING PROTEINS Protein domain Motor Activity Arginine General Biochemistry Genetics and Molecular Biology Article protein aggregation PRION-LIKE DOMAINS LIQUID DROPLETS 03 medical and health sciences Structure-Activity Relationship prion-like domain Stress granule Protein Domains NUCLEAR IMPORT RECEPTOR Cell Line Tumor medicine Animals Humans Amino Acid Sequence FUS FRONTOTEMPORAL LOBAR DEGENERATION Science & Technology Heterogeneous-Nuclear Ribonucleoprotein Group F-H STRESS GRANULES Biology and Life Sciences Cell Biology biology.organism_classification medicine.disease intrinsically disordered protein 030104 developmental biology lcsh:Biology (General) phase transition Nerve Degeneration low-complexity domain LLPS ALS PHASE-SEPARATION |
| Zdroj: | Cell Reports, Vol 24, Iss 3, Pp 529-537.e4 (2018) Cell Reports CELL REPORTS |
| ISSN: | 2211-1247 |
| Popis: | Summary RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins. Graphical Abstract Highlights • Both QGSY and RGG2 domains are necessary for FUS-induced neurodegeneration in flies • Arginine-rich domains interact with QGSY hydrogels and liquid droplets • RGG2 arginines promote phase separation of FUS in vitro and in cells • FUS phase separation behavior in vitro correlates with neurodegeneration in vivo Protein aggregation is a hallmark of ALS. Bogaert et al. describe the molecular interactions between disordered regions of the FUS protein driving its liquid phase behavior, maturation, and neurotoxicity. These findings highlight the physicochemical interactions driving FUS phase separation and give us insights into its misregulation in disease. |
| Databáze: | OpenAIRE |
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