Journal article
Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS
Nature communications, v 11(1), pp 5735-5735
12 Nov 2020
PMID: 33184287
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Protein domains without the usual distribution of amino acids, called low complexity (LC) domains, can be prone to self-assembly into amyloid-like fibrils. Self-assembly of LC domains that are nearly devoid of hydrophobic residues, such as the 214-residue LC domain of the RNA-binding protein FUS, is particularly intriguing from the biophysical perspective and is biomedically relevant due to its occurrence within neurons in amyotrophic lateral sclerosis, frontotemporal dementia, and other neurodegenerative diseases. We report a high-resolution molecular structural model for fibrils formed by the C-terminal half of the FUS LC domain (FUS-LC-C, residues 111-214), based on a density map with 2.62 angstrom resolution from cryo-electron microscopy (cryo-EM). In the FUS-LC-C fibril core, residues 112-150 adopt U-shaped conformations and form two subunits with in-register, parallel cross-beta structures, arranged with quasi-2(1) symmetry. All-atom molecular dynamics simulations indicate that the FUS-LC-C fibril core is stabilized by a plethora of hydrogen bonds involving sidechains of Gln, Asn, Ser, and Tyr residues, both along and transverse to the fibril growth direction, including diverse sidechain-to-backbone, sidechain-to-sidechain, and sidechain-to-water interactions. Nuclear magnetic resonance measurements additionally show that portions of disordered residues 151-214 remain highly dynamic in FUS-LC-C fibrils and that fibrils formed by the N-terminal half of the FUS LC domain (FUS-LC-N, residues 2-108) have the same core structure as fibrils formed by the full-length LC domain. These results contribute to our understanding of the molecular structural basis for amyloid formation by FUS and by LC domains in general. The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.
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Details
- Title
- Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS
- Creators
- Myungwoon Lee - National Institutes of HealthUjjayini Ghosh - National Institute of Diabetes and Digestive and Kidney DiseasesKent R. Thurber - National Institute of Diabetes and Digestive and Kidney DiseasesMasato Kato - The University of Texas Southwestern Medical CenterRobert Tycko - National Institute of Diabetes and Digestive and Kidney Diseases
- Publication Details
- Nature communications, v 11(1), pp 5735-5735
- Publisher
- Springer Nature
- Number of pages
- 14
- Grant note
- Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000593980000001
- Scopus ID
- 2-s2.0-85095934375
- Other Identifier
- 991021229890604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology