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- PDB-6wpq: GNYNVF from hnRNPA2-low complexity domain segment, residues 286-2... -

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Basic information

Entry
Database: PDB / ID: 6wpq
TitleGNYNVF from hnRNPA2-low complexity domain segment, residues 286-291, D290V variant
ComponentsHeterogeneous nuclear ribonucleoprotein A2
KeywordsPROTEIN FIBRIL / amyloidogenic segment / amyloid-like fibril / disease related / multisystem proteinopathy (MSP)
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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / AB INITIO PHASING / Resolution: 1.1 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 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 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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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heterogeneous nuclear ribonucleoprotein A2


Theoretical massNumber of molelcules
Total (without water)7131
Polymers7131
Non-polymers00
Water543
1
A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2

A: Heterogeneous nuclear ribonucleoprotein A2


Theoretical massNumber of molelcules
Total (without water)7,12810
Polymers7,12810
Non-polymers00
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
crystal symmetry operation1_655x+1,y,z1
crystal symmetry operation1_355x-2,y,z1
crystal symmetry operation1_755x+2,y,z1
crystal symmetry operation2_546-x,y-1/2,-z+11
crystal symmetry operation2_646-x+1,y-1/2,-z+11
crystal symmetry operation2_446-x-1,y-1/2,-z+11
crystal symmetry operation2_746-x+2,y-1/2,-z+11
crystal symmetry operation2_846-x+3,y-1/2,-z+11
Unit cell
Length a, b, c (Å)4.780, 19.000, 20.740
Angle α, β, γ (deg.)90.000, 95.710, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide Heterogeneous nuclear ribonucleoprotein A2 / hnRNP A2


Mass: 712.751 Da / Num. of mol.: 1 / Mutation: D290V / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P22626
#2: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: salt: 0.15M Ammonium Acetate, precipitant: 35% MPD, buffer: 0.1M Bis-Tris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.1→20.64 Å / Num. obs: 1329 / % possible obs: 86.5 % / Redundancy: 5.583 % / Biso Wilson estimate: 9.262 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.106 / Rrim(I) all: 0.116 / Χ2: 0.918 / Net I/σ(I): 10.45 / Num. measured all: 7420 / Scaling rejects: 9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.1-1.153.4670.1855.67260180750.9530.21841.7
1.15-1.24.0090.1646.354491811120.9770.18861.9
1.2-1.265.4190.1658.247371441360.9810.18294.4
1.26-1.335.4350.1538.97501421380.9810.1797.2
1.33-1.415.70.1569.837981431400.9770.17297.9
1.41-1.55.5360.1399.916921341250.9810.15393.3
1.5-1.625.6540.12711.147521361330.9770.1497.8
1.62-1.786.5350.11612.7647100990.9920.12699
1.78-1.996.2830.11313.07622101990.9940.12298
1.99-2.36.2860.10613.3161699980.990.11599
2.3-2.816.4550.0813.9949777770.9940.086100
2.81-3.986.1670.114.2337061600.9760.1198.4
3.98-20.646.2160.08714.1823038370.9950.09597.4

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEVERSION Jan 26, 2018 BUILT=20180808data scaling
REFMAC5.8.0230refinement
PDB_EXTRACT3.25data extraction
SHELXDphasing
RefinementMethod to determine structure: AB INITIO PHASING / Resolution: 1.1→20.64 Å / Cor.coef. Fo:Fc: 0.992 / Cor.coef. Fo:Fc free: 0.99 / SU B: 0.676 / SU ML: 0.014 / SU R Cruickshank DPI: 0.0245 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.025 / ESU R Free: 0.026
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1038 133 10 %RANDOM
Rwork0.0742 ---
obs0.0772 1196 86.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 9.96 Å2 / Biso mean: 4.822 Å2 / Biso min: 3.84 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å20 Å2-0.05 Å2
2--0.4 Å20 Å2
3----0.19 Å2
Refinement stepCycle: final / Resolution: 1.1→20.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms51 0 0 3 54
Biso mean---7.3 -
Num. residues----6
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.01152
X-RAY DIFFRACTIONr_bond_other_d0.0010.01844
X-RAY DIFFRACTIONr_angle_refined_deg1.8221.67470
X-RAY DIFFRACTIONr_angle_other_deg0.6571.6596
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.88655
X-RAY DIFFRACTIONr_dihedral_angle_2_deg45.314254
X-RAY DIFFRACTIONr_dihedral_angle_3_deg3.692155
X-RAY DIFFRACTIONr_chiral_restr0.1610.25
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0266
X-RAY DIFFRACTIONr_gen_planes_other00.0218
X-RAY DIFFRACTIONr_rigid_bond_restr3.667396
X-RAY DIFFRACTIONr_sphericity_free4.45952
X-RAY DIFFRACTIONr_sphericity_bonded1.535596
LS refinement shellResolution: 1.103→1.132 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.216 4 -
Rwork0.123 38 -
all-42 -
obs--36.52 %

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