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- PDB-6xfm: Molecular structure of the core of amyloid-like fibrils formed by... -

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Basic information

Entry
Database: PDB / ID: 6xfm
TitleMolecular structure of the core of amyloid-like fibrils formed by residues 111-214 of FUS
ComponentsRNA-binding protein FUS
KeywordsRNA BINDING PROTEIN / PROTEIN FIBRIL / Low complexity domain / Protein aggregation / Amyloid Fibril
Function / homology
Function and homology information


mRNA stabilization / positive regulation of double-strand break repair via homologous recombination / intracellular non-membrane-bounded organelle / regulation of RNA splicing / Processing of Capped Intron-Containing Pre-mRNA / molecular condensate scaffold activity / mRNA Splicing - Major Pathway / RNA splicing / mRNA 3'-UTR binding / transcription coregulator activity ...mRNA stabilization / positive regulation of double-strand break repair via homologous recombination / intracellular non-membrane-bounded organelle / regulation of RNA splicing / Processing of Capped Intron-Containing Pre-mRNA / molecular condensate scaffold activity / mRNA Splicing - Major Pathway / RNA splicing / mRNA 3'-UTR binding / transcription coregulator activity / protein homooligomerization / amyloid fibril formation / transcription coactivator activity / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / DNA binding / RNA binding / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytoplasm
Similarity search - Function
TAF15/EWS/TLS family / Zinc finger domain / Zn-finger in Ran binding protein and others / Zinc finger RanBP2 type profile. / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. ...TAF15/EWS/TLS family / Zinc finger domain / Zn-finger in Ran binding protein and others / Zinc finger RanBP2 type profile. / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
RNA-binding protein FUS
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.62 Å
AuthorsTycko, R. / Lee, M. / Ghosh, U. / Thurber, K. / Kato, M.
CitationJournal: Nat Commun / Year: 2020
Title: Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS.
Authors: Myungwoon Lee / Ujjayini Ghosh / Kent R Thurber / Masato Kato / Robert Tycko /
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 ...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 Å 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-β structures, arranged with quasi-2 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.
History
DepositionJun 15, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
1: RNA-binding protein FUS
2: RNA-binding protein FUS
3: RNA-binding protein FUS
4: RNA-binding protein FUS
5: RNA-binding protein FUS
6: RNA-binding protein FUS
7: RNA-binding protein FUS
8: RNA-binding protein FUS


Theoretical massNumber of molelcules
Total (without water)80,1988
Polymers80,1988
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, negative stained TEM and dark-field TEM
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area23240 Å2
ΔGint-18 kcal/mol
Surface area12450 Å2
Number of models14

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Components

#1: Protein
RNA-binding protein FUS / / 75 kDa DNA-pairing protein / Oncogene FUS / Oncogene TLS / POMp75 / Translocated in liposarcoma protein


Mass: 10024.784 Da / Num. of mol.: 8 / Fragment: low complexity domain (UNP residues 111-214)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FUS, TLS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P35637

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: HELICAL ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: FUS low complexity sequence / Type: COMPLEX
Details: C-terminal domain of FUS low complexity domain (111-214)
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 40.4 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4 / Details: 20 mM 2-mercaptoethanol, 0.1 mM PMSF
Buffer componentConc.: 20 mM / Name: Tris HCl / Formula: C4H11NO3
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: The grid was glow discharged immediately before use.
Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 99 % / Chamber temperature: 93 K
Details: Preblot for 10 seconds and blot for 5 seconds before plunging

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 6 sec. / Electron dose: 47 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 2404
Details: 58185 fibril segments were manually selected from 2404 micrographs
Image scansWidth: 3800 / Height: 3700 / Movie frames/image: 30

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2SerialEMimage acquisition
4RELION3CTF correction
7Cootmodel fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
11RELION3classification
12RELION33D reconstruction
13PHENIXmodel refinement
14UCSF Chimeramodel refinement
15X-PLORXplor-NIHmodel refinement
Image processingDetails: Gatan Imaging Filter (GIF) Quantum LS
CTF correctionDetails: Gctf / Type: NONE
Helical symmertyAngular rotation/subunit: -2 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2
Particle selectionNum. of particles selected: 499206
Details: 499206 of particles were extracted from the 58185 fibril segments using a 400-pixel box size and 91.6% overlap.
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 275520 / Algorithm: FOURIER SPACE
Details: 3D refinement and post-processing were performed with 21 (screw) symmetry
Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER
Details: Manually generated model was fit into the density using PHENIX and UCSF Chimera. Further refinements were performed using Xplor-NIH.

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