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- PDB-7zir: Cryo-EM structure of hnRNPDL amyloid fibrils -

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Basic information

Entry
Database: PDB / ID: 7zir
TitleCryo-EM structure of hnRNPDL amyloid fibrils
ComponentsHeterogeneous nuclear ribonucleoprotein D-like
KeywordsRNA BINDING PROTEIN / Amyloid / Protein aggregation / Alternative splicing / Exon / Prion-like / LGMD1G / cryoEM structure
Function / homology
Function and homology information


poly(G) binding / poly(A) binding / RNA processing / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / spliceosomal complex / single-stranded DNA binding / regulation of gene expression / double-stranded DNA binding / DNA binding / RNA binding ...poly(G) binding / poly(A) binding / RNA processing / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / spliceosomal complex / single-stranded DNA binding / regulation of gene expression / double-stranded DNA binding / DNA binding / RNA binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
hnRNP DL, RNA recognition motif 1 / 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
Heterogeneous nuclear ribonucleoprotein D-like
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsGarcia-Pardo, J. / Chaves-Sanjuan, A. / Bartolome-Nafria, A. / Gil-Garcia, M. / Visentin, C. / Bolognesi, M. / Ricagno, S. / Ventura, S.
Funding support Spain, 3items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)IJC2019-041039-I Spain
Ministerio de Ciencia e Innovacion (MCIN)PID2019-105017RB-I00 Spain
Generalitat de CatalunyaICREA-Academia 2020 Spain
CitationJournal: Nat Commun / Year: 2023
Title: Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3.
Authors: Javier Garcia-Pardo / Andrea Bartolomé-Nafría / Antonio Chaves-Sanjuan / Marcos Gil-Garcia / Cristina Visentin / Martino Bolognesi / Stefano Ricagno / Salvador Ventura /
Abstract: hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative ...hnRNPDL is a ribonucleoprotein (RNP) involved in transcription and RNA-processing that hosts missense mutations causing limb-girdle muscular dystrophy D3 (LGMD D3). Mammalian-specific alternative splicing (AS) renders three natural isoforms, hnRNPDL-2 being predominant in humans. We present the cryo-electron microscopy structure of full-length hnRNPDL-2 amyloid fibrils, which are stable, non-toxic, and bind nucleic acids. The high-resolution amyloid core consists of a single Gly/Tyr-rich and highly hydrophilic filament containing internal water channels. The RNA binding domains are located as a solenoidal coat around the core. The architecture and activity of hnRNPDL-2 fibrils are reminiscent of functional amyloids, our results suggesting that LGMD D3 might be a loss-of-function disease associated with impaired fibrillation. Strikingly, the fibril core matches exon 6, absent in the soluble hnRNPDL-3 isoform. This provides structural evidence for AS controlling hnRNPDL assembly by precisely including/skipping an amyloid exon, a mechanism that holds the potential to generate functional diversity in RNPs.
History
DepositionApr 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: 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 1.2Dec 13, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Heterogeneous nuclear ribonucleoprotein D-like
A: Heterogeneous nuclear ribonucleoprotein D-like
E: Heterogeneous nuclear ribonucleoprotein D-like
D: Heterogeneous nuclear ribonucleoprotein D-like
B: Heterogeneous nuclear ribonucleoprotein D-like


Theoretical massNumber of molelcules
Total (without water)229,0215
Polymers229,0215
Non-polymers00
Water90150
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, Thioflavin-T positive amyloid fibrils
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Heterogeneous nuclear ribonucleoprotein D-like / hnRNP D-like / hnRNP DL / AU-rich element RNA-binding factor / JKT41-binding protein / Protein laAUF1


Mass: 45804.266 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HNRNPDL, HNRPDL, JKTBP / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O14979
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: hnRNPDL-2 amyloid fibrils / Type: COMPLEX
Details: Fibril structure of the recombinantly produced full-lenght Heterogeneous ribonucleoprotein D-like (hnRNPDL) isoform 2
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
150 mMHEPES1
2150 mMNaCl1
SpecimenConc.: 0.23 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Diluted sample of hnRNPDL2 amyloid fibrils formed under native conditions.
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 120000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1114

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
1RELION3.1particle selection
4CTFFIND4CTF correction
7Cootmodel fitting
11RELION3.1classification
12RELION3.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -4.8 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 158493
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 54490 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: BACKBONE TRACE / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0022150
ELECTRON MICROSCOPYf_angle_d0.3232920
ELECTRON MICROSCOPYf_dihedral_angle_d9.02685
ELECTRON MICROSCOPYf_chiral_restr0.032195
ELECTRON MICROSCOPYf_plane_restr0.001415

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