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- EMDB-21871: hnRNPA2 Low complexity domain (LCD) determined by cryoEM -

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Basic information

Entry
Database: EMDB / ID: EMD-21871
TitlehnRNPA2 Low complexity domain (LCD) determined by cryoEM
Map data
Sample
  • Complex: heterogeneous nuclear ribonucleo-protein A2
    • Protein or peptide: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
KeywordsRibinucleoprotein / RNA binding protein / Low complexity domain / PROTEIN FIBRIL
Function / homology
Function and homology information


: / 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 ...: / 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 / mRNA export from nucleus / Cajal body / pre-mRNA intronic binding / catalytic step 2 spliceosome / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / mRNA Splicing - Major Pathway / bioluminescence / generation of precursor metabolites and energy / mRNA 3'-UTR binding / molecular condensate scaffold activity / spliceosomal complex / mRNA splicing, via spliceosome / nuclear matrix / mRNA processing / chromosome, telomeric region / ribonucleoprotein complex / negative regulation of transcription by RNA polymerase II / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / 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 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. ...hnRNP A2/B1, RNA recognition motif 1 / Heterogeneous nuclear ribonucleoprotein A1/A2, C-terminal / Heterogeneous nuclear ribonucleoprotein A1, LC domain / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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 / MCherry fluorescent protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLu J / Cao Q
Funding support United States, 2 items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)1616265 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG054022 United States
CitationJournal: Nat Commun / Year: 2020
Title: CryoEM structure of the low-complexity domain of hnRNPA2 and its conversion to pathogenic amyloid.
Authors: Jiahui Lu / Qin Cao / Michael P Hughes / Michael R Sawaya / David R Boyer / Duilio Cascio / David S Eisenberg /
Abstract: hnRNPA2 is a human ribonucleoprotein (RNP) involved in RNA metabolism. It forms fibrils both under cellular stress and in mutated form in neurodegenerative conditions. Previous work established that ...hnRNPA2 is a human ribonucleoprotein (RNP) involved in RNA metabolism. It forms fibrils both under cellular stress and in mutated form in neurodegenerative conditions. Previous work established that the C-terminal low-complexity domain (LCD) of hnRNPA2 fibrillizes under stress, and missense mutations in this domain are found in the disease multisystem proteinopathy (MSP). However, little is known at the atomic level about the hnRNPA2 LCD structure that is involved in those processes and how disease mutations cause structural change. Here we present the cryo-electron microscopy (cryoEM) structure of the hnRNPA2 LCD fibril core and demonstrate its capability to form a reversible hydrogel in vitro containing amyloid-like fibrils. Whereas these fibrils, like pathogenic amyloid, are formed from protein chains stacked into β-sheets by backbone hydrogen bonds, they display distinct structural differences: the chains are kinked, enabling non-covalent cross-linking of fibrils and disfavoring formation of pathogenic steric zippers. Both reversibility and energetic calculations suggest these fibrils are less stable than pathogenic amyloid. Moreover, the crystal structure of the disease-mutation-containing segment (D290V) of hnRNPA2 suggests that the replacement fundamentally alters the fibril structure to a more stable energetic state. These findings illuminate how molecular interactions promote protein fibril networks and how mutation can transform fibril structure from functional to a pathogenic form.
History
DepositionApr 29, 2020-
Header (metadata) releaseAug 26, 2020-
Map releaseAug 26, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.7
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 3.7
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wqk
  • Surface level: 3.7
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6wqk
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21871.png

Downloads & links

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Map

FileDownload / File: emd_21871.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 128 pix.
= 136.192 Å		1.06 Å/pix.
x 128 pix.
= 136.192 Å		1.06 Å/pix.
x 128 pix.
= 136.192 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.7 / Movie #1: 3.7
Minimum - Maximum-9.230973000000001 - 12.669366
Average (Standard dev.)0.000000000005091 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-64-64-64
Dimensions128128128
Spacing128128128
CellA=B=C: 136.192 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0641.0641.064
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z136.192136.192136.192
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S321
start NC/NR/NS-64-64-64
NC/NR/NS128128128
D min/max/mean-9.23112.6690.000

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Supplemental data

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Sample components

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Entire : heterogeneous nuclear ribonucleo-protein A2

EntireName: heterogeneous nuclear ribonucleo-protein A2
Components
  • Complex: heterogeneous nuclear ribonucleo-protein A2
    • Protein or peptide: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera

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Supramolecule #1: heterogeneous nuclear ribonucleo-protein A2

SupramoleculeName: heterogeneous nuclear ribonucleo-protein A2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoprote...

MacromoleculeName: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.666625 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSYYHHHHHH DYDIPTTENL YFQGAMVSKG EEDNMAIIKE FMRFKVHMEG SVNGHEFEIE GEGEGRPYEG TQTAKLKVTK GGPLPFAWD ILSPQFMYGS KAYVKHPADI PDYLKLSFPE GFKWERVMNF EDGGVVTVTQ DSSLQDGEFI YKVKLRGTNF P SDGPVMQK ...String:
MSYYHHHHHH DYDIPTTENL YFQGAMVSKG EEDNMAIIKE FMRFKVHMEG SVNGHEFEIE GEGEGRPYEG TQTAKLKVTK GGPLPFAWD ILSPQFMYGS KAYVKHPADI PDYLKLSFPE GFKWERVMNF EDGGVVTVTQ DSSLQDGEFI YKVKLRGTNF P SDGPVMQK KTMGWEASSE RMYPEDGALK GEIKQRLKLK DGGHYDAEVK TTYKAKKPVQ LPGAYNVNIK LDITSHNEDY TI VEQYERA EGRHSTGGMD ELYKAMDPMQ EVQSSRSGRG GNFGFGDSRG GGGNFGPGPG SNFRGGSDGY GSGRGFGDGY NGY GGGPGG GNFGGSPGYG GGRGGYGGGG PGYGNQGGGY GGGYDNYGGG NYGSGNYNDF GNYNQQPSNY GPMKSGNFGG SRNM GGPYG GGNYGPGGSG GSGGYGGRSR Y

UniProtKB: MCherry fluorescent protein, 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 IS (4k x 4k) / Average electron dose: 1.15 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.81 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.88 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 132571
Startup modelType of model: OTHER / Details: an elongated Gaussian blob
Final angle assignmentType: NOT APPLICABLE

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