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- PDB-8du2: HnRNPA2 D290V LCD PM1 -

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Basic information

Entry
Database: PDB / ID: 8du2
TitleHnRNPA2 D290V LCD PM1
ComponentsHeterogeneous nuclear ribonucleoproteins A2/B1
KeywordsPROTEIN FIBRIL / Amyloid
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 / mRNA 3'-UTR binding / spliceosomal complex / molecular condensate scaffold activity / 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 / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsEisenberg, D.S. / Lu, J. / Ge, P. / Boyer, D.R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)NIH 1R01AG070895 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)NIH R01 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
DepositionJul 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 2, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 14, 2024Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heterogeneous nuclear ribonucleoproteins A2/B1
B: Heterogeneous nuclear ribonucleoproteins A2/B1
C: Heterogeneous nuclear ribonucleoproteins A2/B1
D: Heterogeneous nuclear ribonucleoproteins A2/B1
E: Heterogeneous nuclear ribonucleoproteins A2/B1
F: Heterogeneous nuclear ribonucleoproteins A2/B1
G: Heterogeneous nuclear ribonucleoproteins A2/B1
H: Heterogeneous nuclear ribonucleoproteins A2/B1
I: Heterogeneous nuclear ribonucleoproteins A2/B1
J: Heterogeneous nuclear ribonucleoproteins A2/B1


Theoretical massNumber of molelcules
Total (without water)153,91810
Polymers153,91810
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
SymmetryHelical symmetry: (Circular symmetry: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 10 / Rise per n subunits: 2.45 Å / Rotation per n subunits: 179.63 °)
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "G"
d_8ens_1chain "H"
d_9ens_1chain "I"
d_10ens_1chain "J"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLYGLYA263 - 316
d_21ens_1GLYGLYB263 - 316
d_31ens_1GLYGLYC263 - 316
d_41ens_1GLYGLYD263 - 316
d_51ens_1GLYGLYE263 - 316
d_61ens_1GLYGLYF263 - 316
d_71ens_1GLYGLYG263 - 316
d_81ens_1GLYGLYH263 - 316
d_91ens_1GLYGLYI263 - 316
d_101ens_1GLYGLYJ263 - 316

NCS oper:
IDCodeMatrixVector
1given(-0.999997976228, -0.00181534699113, -0.000867211595422), (0.00181749730905, -0.999995260088, -0.00248525771207), (-0.000862695879805, -0.00248682883722, 0.999996535713)345.404012479, 345.204220699, 3.04707550017
2given(-0.99994837739, 0.0101262936665, -0.000837097775263), (-0.0101241746871, -0.999945629152, -0.00249796455412), (-0.000862347384191, -0.00248936067856, 0.999996529714)343.329040726, 347.257576205, -1.84450561155
3given(0.999969352522, 0.00777938914999, 0.000880409805382), (-0.00778155526432, 0.999966637359, 0.00248426385782), (-0.000861054377285, -0.00249103867895, 0.99999652665)-1.47084503539, 0.789310619533, 5.49352728043
4given(0.999870211559, -0.0160899714191, 0.000820278838137), (0.0160878715801, 0.999867443208, 0.00250527463582), (-0.000860479901892, -0.00249175293952, 0.999996525365)2.67674504128, -3.31370695283, -4.29046104564
5given(-0.999905131068, -0.0137450947152, -0.000895117549309), (0.0137472768824, -0.999902428398, -0.00247912544431), (-0.000860954397213, -0.00249119568112, 0.999996526345)347.452032771, 343.129814137, 7.94053476914
6given(-0.999756363253, 0.0220581252823, -0.00080823527398), (-0.0220560394556, -0.999753598603, -0.00250463639503), (-0.000863283707068, -0.00248619970447, 0.99999653677)341.231323996, 349.283306428, -6.73792202879
7given(0.999805330168, 0.0197097464741, 0.000909758771181), (-0.0197119446675, 0.999802639665, 0.00247405654789), (-0.000860816193564, -0.00249150803827, 0.999996525686)-3.50708548632, 2.8768704466, 10.3865610327
8given(0.999607128778, -0.0280171102765, 0.000793490388341), (0.0280150406358, 0.999604352391, 0.00250921902573), (-0.000863477511918, -0.00248600356031, 0.99999653709)4.78556964774, -5.32584866571, -9.18391592202
9given(-0.9994222994, 0.0339774207035, -0.000776108590845), (-0.0339753693686, -0.99941949632, -0.00251885935447), (-0.000861242400932, -0.00249103563187, 0.999996526495)339.110805467, 351.283546692, -11.6294405936

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Components

#1: Protein
Heterogeneous nuclear ribonucleoproteins A2/B1 / hnRNP A2/B1


Mass: 15391.775 Da / Num. of mol.: 10 / Fragment: LCD (UNP residues 193-353) / Mutation: D290V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HNRNPA2B1, HNRPA2B1 / Production host: Escherichia coli (E. coli) / References: 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: Fibrils of hnRNPA2 D290V LCD PM1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 36 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
Helical symmertyAngular rotation/subunit: 179.63 ° / Axial rise/subunit: 2.45 Å / Axial symmetry: C1
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 5675 / Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 93.47 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034010
ELECTRON MICROSCOPYf_angle_d0.4145360
ELECTRON MICROSCOPYf_dihedral_angle_d9.1071380
ELECTRON MICROSCOPYf_chiral_restr0.037360
ELECTRON MICROSCOPYf_plane_restr0.002800
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000523232970225
ens_1d_3AELECTRON MICROSCOPYNCS constraints0.000509318505376
ens_1d_4AELECTRON MICROSCOPYNCS constraints0.000512193407214
ens_1d_5AELECTRON MICROSCOPYNCS constraints0.000513259993321
ens_1d_6AELECTRON MICROSCOPYNCS constraints0.000519933201535
ens_1d_7AELECTRON MICROSCOPYNCS constraints0.000514904114057
ens_1d_8AELECTRON MICROSCOPYNCS constraints0.000525786312853
ens_1d_9AELECTRON MICROSCOPYNCS constraints0.000514980834031
ens_1d_10AELECTRON MICROSCOPYNCS constraints0.000514703977818

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