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- PDB-6wqk: hnRNPA2 Low complexity domain (LCD) determined by cryoEM -

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Entry
Database: PDB / ID: 6wqk
TitlehnRNPA2 Low complexity domain (LCD) determined by cryoEM
ComponentsMCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
KeywordsPROTEIN FIBRIL / Ribinucleoprotein / RNA binding protein / Low complexity domain
Function / homology
Function and homology information


miRNA transport / RNA transport / positive regulation of telomere maintenance via telomere lengthening / DNA geometric change / primary miRNA processing / N6-methyladenosine-containing RNA reader activity / single-stranded telomeric DNA binding / G-rich strand telomeric DNA binding / miRNA binding / Processing of Capped Intron-Containing Pre-mRNA ...miRNA transport / RNA transport / positive regulation of telomere maintenance via telomere lengthening / DNA geometric change / primary miRNA processing / N6-methyladenosine-containing RNA reader activity / single-stranded telomeric DNA binding / G-rich strand telomeric DNA binding / miRNA binding / Processing of Capped Intron-Containing Pre-mRNA / mRNA transport / mRNA export from nucleus / Cajal body / DNA polymerase binding / catalytic step 2 spliceosome / mRNA Splicing - Major Pathway / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / bioluminescence / mRNA 3'-UTR binding / generation of precursor metabolites and energy / spliceosomal complex / molecular condensate scaffold activity / mRNA splicing, via spliceosome / nuclear matrix / mRNA processing / chromosome, telomeric region / ribonucleoprotein complex / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / nucleus / membrane / 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 speciesAnaplasma marginale (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLu, J. / Cao, Q. / Hughes, M.P. / Sawaya, M.R. / Boyer, D.R. / Cascio, D. / Eisenberg, D.S.
Funding support United States, 2items
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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 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
A: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
B: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
C: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
D: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera
E: MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera


Theoretical massNumber of molelcules
Total (without water)228,3335
Polymers228,3335
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy, Negative stain EM proves the presence of fibrils
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18320 Å2
ΔGint-60 kcal/mol
Surface area10480 Å2
SymmetryHelical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 5 / Rise per n subunits: 4.81 Å / Rotation per n subunits: -2.88 °)

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Components

#1: Protein
MCherry fluorescent protein,Heterogeneous nuclear ribonucleoproteins A2/B1 chimera / hnRNP A2/B1


Mass: 45666.625 Da / Num. of mol.: 5 / Fragment: low complexity domain (UNP residues 193-353)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Anaplasma marginale (bacteria), (gene. exp.) Homo sapiens (human)
Gene: mCherry, HNRNPA2B1, HNRPA2B1 / Production host: Escherichia coli (E. coli) / References: UniProt: X5DSL3, UniProt: P22626

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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: heterogeneous nuclear ribonucleo-protein A2 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 1.15 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3724: / Classification: refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
19PHENIXdev_3724model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.88 ° / Axial rise/subunit: 4.81 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 132571 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032135
ELECTRON MICROSCOPYf_angle_d0.5692860
ELECTRON MICROSCOPYf_dihedral_angle_d4.843330
ELECTRON MICROSCOPYf_chiral_restr0.039185
ELECTRON MICROSCOPYf_plane_restr0.004430

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