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- EMDB-14738: Cryo-EM structure of hnRNPDL amyloid fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-14738
TitleCryo-EM structure of hnRNPDL amyloid fibrils
Map datasharped
Sample
  • Complex: hnRNPDL-2 amyloid fibrils
    • Protein or peptide: Heterogeneous nuclear ribonucleoprotein D-like
  • Ligand: water
KeywordsAmyloid / Protein aggregation / Alternative splicing / Exon / Prion-like / LGMD1G / cryoEM structure / RNA BINDING PROTEIN
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 / double-stranded DNA binding / regulation of gene expression / chromatin / DNA 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 / double-stranded DNA binding / regulation of gene expression / chromatin / 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)
Methodhelical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsChaves-Sanjuan A / Garcia-Pardo J / Bartolome-Nafria A / Gil-Garcia M / Visentin C / Bolognesi M / Ricagno S / Ventura S
Funding support Spain, 3 items
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, 2022-
Header (metadata) releaseDec 28, 2022-
Map releaseDec 28, 2022-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14738.png

Downloads & links

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Map

FileDownload / File: emd_14738.map.gz / Format: CCP4 / Size: 209.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharped
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 380 pix.
= 337.82 Å		0.89 Å/pix.
x 380 pix.
= 337.82 Å		0.89 Å/pix.
x 380 pix.
= 337.82 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.889 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.15189321 - 0.31168008
Average (Standard dev.)0.00025083244 (±0.0051423223)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions380380380
Spacing380380380
CellA=B=C: 337.82 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharped

Fileemd_14738_additional_1.map
Annotationunsharped
Projections & Slices
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Slices (1/2)
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Half map: half 1

Fileemd_14738_half_map_1.map
Annotationhalf 1
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Histogram

Histogram (log scale)

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Half map: half 2

Fileemd_14738_half_map_2.map
Annotationhalf 2
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Sample components

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Entire : hnRNPDL-2 amyloid fibrils

EntireName: hnRNPDL-2 amyloid fibrils
Components
  • Complex: hnRNPDL-2 amyloid fibrils
    • Protein or peptide: Heterogeneous nuclear ribonucleoprotein D-like
  • Ligand: water

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Supramolecule #1: hnRNPDL-2 amyloid fibrils

SupramoleculeName: hnRNPDL-2 amyloid fibrils / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Fibril structure of the recombinantly produced full-lenght Heterogeneous ribonucleoprotein D-like (hnRNPDL) isoform 2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heterogeneous nuclear ribonucleoprotein D-like

MacromoleculeName: Heterogeneous nuclear ribonucleoprotein D-like / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.804266 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MHHHHHHGSL QDSEVNQEAK PEVKPEVKPE THINLKVSDG SSEIFFKIKK TTPLRRLMEA FAKRQGKEMD SLTFLYDGIE IQADQTPED LDMEDNDIIE AHREQIGGED MNEYSNIEEF AEGSKINASK NQQDDGKMFI GGLSWDTSKK DLTEYLSRFG E VVDCTIKT ...String:
MHHHHHHGSL QDSEVNQEAK PEVKPEVKPE THINLKVSDG SSEIFFKIKK TTPLRRLMEA FAKRQGKEMD SLTFLYDGIE IQADQTPED LDMEDNDIIE AHREQIGGED MNEYSNIEEF AEGSKINASK NQQDDGKMFI GGLSWDTSKK DLTEYLSRFG E VVDCTIKT DPVTGRSRGF GFVLFKDAAS VDKVLELKEH KLDGKLIDPK RAKALKGKEP PKKVFVGGLS PDTSEEQIKE YF GAFGEIE NIELPMDTKT NERRGFCFIT YTDEEPVKKL LESRYHQIGS GKCEIKVAQP KEVYRQQQQQ QKGGRGAAAG GRG GTRGRG RGQGQNWNQG FNNYYDQGYG NYNSAYGGDQ NYSGYGGYDY TGYNYGNYGY GQGYADYSGQ QSTYGKASRG GGNH QNNYQ PY

UniProtKB: Heterogeneous nuclear ribonucleoprotein D-like

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 50 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration0.23 mg/mL
BufferpH: 7.5 / Component:
ConcentrationName
50.0 mMHEPES
150.0 mMNaCl
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV
DetailsDiluted sample of hnRNPDL2 amyloid fibrils formed under native conditions.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Number grids imaged: 1 / Number real images: 1114 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 120000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -4.8 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 54490
Segment selectionNumber selected: 158493 / Software - Name: RELION (ver. 3.1)
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: BACKBONE TRACE
Output model

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

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