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- EMDB-28014: HnRNPA2 D290V LCD PM3 -

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Basic information

Entry
Database: EMDB / ID: EMD-28014
TitleHnRNPA2 D290V LCD PM3
Map data
Sample
  • Complex: Fibrils of hnRNPA2 D290V LCD PM3
    • Protein or peptide: Heterogeneous nuclear ribonucleoproteins A2/B1
KeywordsAmyloid / PROTEIN FIBRIL
Function / homology
Function and homology information


positive regulation of telomerase RNA reverse transcriptase activity / miRNA transport / positive regulation of telomere maintenance via telomere lengthening / RNA transport / G-quadruplex DNA unwinding / primary miRNA processing / single-stranded telomeric DNA binding / N6-methyladenosine-containing RNA reader activity / G-rich strand telomeric DNA binding / miRNA binding ...positive regulation of telomerase RNA reverse transcriptase activity / miRNA transport / positive regulation of telomere maintenance via telomere lengthening / RNA transport / G-quadruplex DNA unwinding / primary miRNA processing / single-stranded telomeric DNA binding / N6-methyladenosine-containing RNA reader activity / G-rich strand telomeric DNA binding / miRNA binding / negative regulation of mRNA splicing, via spliceosome / Processing of Capped Intron-Containing Pre-mRNA / mRNA transport / Cajal body / mRNA export from nucleus / pre-mRNA intronic binding / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / catalytic step 2 spliceosome / molecular condensate scaffold activity / mRNA Splicing - Major Pathway / mRNA 3'-UTR binding / spliceosomal complex / mRNA processing / mRNA splicing, via spliceosome / nuclear matrix / chromosome, telomeric region / ribonucleoprotein complex / negative regulation of transcription by RNA polymerase II / RNA binding / extracellular exosome / nucleoplasm / membrane / identical protein binding / nucleus / cytoplasm
Similarity search - Function
hnRNP A2/B1, RNA recognition motif 1 / Heterogeneous nuclear ribonucleoprotein A1/A2, C-terminal / Heterogeneous nuclear ribonucleoprotein A1, LC domain / 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 ribonucleoproteins A2/B1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsEisenberg DS / Lu J / Ge P / Boyer DR
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG070895 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG048120 United States
CitationJournal: J Biol Chem / Year: 2024
Title: Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.
Authors: Jiahui Lu / Peng Ge / Michael R Sawaya / Michael P Hughes / David R Boyer / Qin Cao / Romany Abskharon / Duilio Cascio / Einav Tayeb-Fligelman / David S Eisenberg /
Abstract: Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, ...Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.
History
DepositionSep 1, 2022-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateFeb 14, 2024-
Current statusFeb 14, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28014.png

Downloads & links

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Map

FileDownload / File: emd_28014.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.078 Å
Density
Contour LevelBy AUTHOR: 5.186
Minimum - Maximum-20.271308999999999 - 22.005737
Average (Standard dev.)0.6450702 (±2.5134792)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin-64-64-64
Dimensions128128128
Spacing128128128
CellA=B=C: 137.984 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_28014_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_28014_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Fibrils of hnRNPA2 D290V LCD PM3

EntireName: Fibrils of hnRNPA2 D290V LCD PM3
Components
  • Complex: Fibrils of hnRNPA2 D290V LCD PM3
    • Protein or peptide: Heterogeneous nuclear ribonucleoproteins A2/B1

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Supramolecule #1: Fibrils of hnRNPA2 D290V LCD PM3

SupramoleculeName: Fibrils of hnRNPA2 D290V LCD PM3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heterogeneous nuclear ribonucleoproteins A2/B1

MacromoleculeName: Heterogeneous nuclear ribonucleoproteins A2/B1 / type: protein_or_peptide / ID: 1 / Number of copies: 15 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.391775 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQEVQSSRSG RGGNFGFGDS RGGGGNFGPG PGSNFRGGSD GYGSGRGFGD GYNGYGGGPG GGNFGGSPGY GGGRGGYGGG GPGYGNQGG GYGGGYDNYG GGNYGSGNYN VFGNYNQQPS NYGPMKSGNF GGSRNMGGPY GGGNYGPGGS GGSGGYGGRS R Y

UniProtKB: Heterogeneous nuclear ribonucleoproteins A2/B1

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 5.0 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 36.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Gaussian blob
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.88 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.72 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 16114

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