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- PDB-7sp1: RNA-induced tau amyloid fibril -

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Basic information

Entry
Database: PDB / ID: 7sp1
TitleRNA-induced tau amyloid fibril
Components
  • Isoform Tau-F of Microtubule-associated protein tau
  • RNA (5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
KeywordsPROTEIN FIBRIL/RNA / amyloid fibril / complex / PROTEIN FIBRIL-RNA complex
Function / homologyActivation of AMPK downstream of NMDARs / PKR-mediated signaling / RNA / Isoform Tau-F of Microtubule-associated protein tau
Function and homology information
Biological speciesHomo sapiens (human)
Mus (mice)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsAbskharon, R. / Sawaya, M.R. / Boyer, D.R. / Eisenberg, D.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01 AG029430 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1 AG054022 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation.
Authors: Romany Abskharon / Michael R Sawaya / David R Boyer / Qin Cao / Binh A Nguyen / Duilio Cascio / David S Eisenberg /
Abstract: In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms in autopsied brains. Evidence suggests that RNA aids ...In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms in autopsied brains. Evidence suggests that RNA aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at the level of atomic structure. Here, we present the 3.4-Å resolution structure of fibrils of full-length recombinant tau protein in the presence of RNA, determined by electron cryomicroscopy (cryo-EM). The structure reveals the familiar in-register cross-β amyloid scaffold but with a small fibril core spanning residues Glu391 to Ala426, a region disordered in the fuzzy coat in all previously studied tau polymorphs. RNA is bound on the fibril surface to the positively charged residues Arg406 and His407 and runs parallel to the fibril axis. The fibrils dissolve when RNase is added, showing that RNA is necessary for fibril integrity. While this structure cannot exist simultaneously with the tau fibril structures extracted from patients’ brains, it could conceivably account for the nucleating effects of RNA cofactors followed by remodeling as fibrils mature.
History
DepositionNov 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2022Group: Database references / Category: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jun 5, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Tau-F of Microtubule-associated protein tau
P: RNA (5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
Q: RNA (5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
B: Isoform Tau-F of Microtubule-associated protein tau
C: Isoform Tau-F of Microtubule-associated protein tau
D: Isoform Tau-F of Microtubule-associated protein tau
E: Isoform Tau-F of Microtubule-associated protein tau
F: Isoform Tau-F of Microtubule-associated protein tau
G: Isoform Tau-F of Microtubule-associated protein tau
H: Isoform Tau-F of Microtubule-associated protein tau
I: Isoform Tau-F of Microtubule-associated protein tau
J: Isoform Tau-F of Microtubule-associated protein tau
K: Isoform Tau-F of Microtubule-associated protein tau
L: Isoform Tau-F of Microtubule-associated protein tau
M: Isoform Tau-F of Microtubule-associated protein tau
N: Isoform Tau-F of Microtubule-associated protein tau
O: Isoform Tau-F of Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)695,29217
Polymers695,29217
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
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"
d_11ens_1chain "K"
d_12ens_1chain "L"
d_13ens_1chain "M"
d_14ens_1chain "N"
d_15ens_1chain "O"
d_1ens_2chain "P"
d_2ens_2chain "Q"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLUALAA1 - 36
d_21ens_1GLUALAD1 - 36
d_31ens_1GLUALAE1 - 36
d_41ens_1GLUALAF1 - 36
d_51ens_1GLUALAG1 - 36
d_61ens_1GLUALAH1 - 36
d_71ens_1GLUALAI1 - 36
d_81ens_1GLUALAJ1 - 36
d_91ens_1GLUALAK1 - 36
d_101ens_1GLUALAL1 - 36
d_111ens_1GLUALAM1 - 36
d_121ens_1GLUALAN1 - 36
d_131ens_1GLUALAO1 - 36
d_141ens_1GLUALAP1 - 36
d_151ens_1GLUALAQ1 - 36
d_11ens_2AAB
d_21ens_2AAC

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.999589383913, -0.0286528163805, 0.000282281034092), (0.0286529135005, 0.999589361022, -0.000346236317938), (-0.000272244472855, 0.000354182321788, 0.999999900219)1.9495555912, -1.8904736999, -4.79734250822
2given(-0.999897158661, 0.0143412722233, -3.50432557E-6), (-0.0143412722792, -0.999897158531, 1.648664992E-5), (-3.26752565E-6, 1.653521089E-5, 0.999999999858)134.700340807, 136.644507452, -2.39585603619
3given(0.998362114562, 0.0572106239745, -0.000180862745246), (-0.0572105832629, 0.99836210842, 0.000222785077385), (0.000193312184968, -0.000212072917805, 0.999999958828)-3.75363789108, 3.97784043373, 9.58291756934
4given(-0.997427767395, 0.07167868764, 0.000120699668001), (-0.0716787094868, -0.997427755484, -0.000187609094468), (0.000106941625261, -0.000195778116676, 0.999999975117)130.632589441, 140.379449969, -11.9709337499
5given(0.998358212641, -0.0572782507356, 0.000285034017211), (0.057278344807, 0.998358192196, -0.00033360234472), (-0.000265457887391, 0.000349380917327, 0.999999903733)3.97438637943, -3.74975957579, -9.58750014923
6given(0.996305583497, -0.085878849282, 8.682566393E-5), (0.0858788511142, 0.996305586967, -1.759236787E-5), (-8.499408176E-5, 2.49838626E-5, 0.999999996076)6.07002290315, -5.57394079111, -14.3684029494
7given(-0.999897369839, -0.0143265413375, -1.58917949E-6), (0.0143265413389, -0.99989736984, -8.2097708E-7), (-1.57725463E-6, -8.4366027E-7, 0.999999999998)136.644673073, 134.701290547, 2.39516937183
8given(-0.994969278424, 0.100180267194, 0.000221491011067), (-0.100180332403, -0.994969249445, -0.00030603708977), (0.000189717867616, -0.000326686545492, 0.999999928642)128.525142644, 142.157644961, -16.7577310253
9given(0.999591733909, 0.0285719968861, -8.058983631E-5), (-0.0285719830925, 0.999591723533, 0.000167408611847), (8.534013171E-5, -0.000165037653146, 0.99999998274)-1.90251426059, 1.95628124479, 4.7964646716
10given(-0.999080129089, -0.0428822712026, 8.047920997E-5), (0.04288225698, -0.999080118335, -0.00017083184971), (8.773083633E-5, -0.000167223576297, 0.99999998217)138.519109812, 132.718580587, 7.19138804332
11given(-0.999111868911, 0.0421296001563, 0.000755110822012), (-0.042131596499, -0.999107981448, -0.00285831810575), (0.000634017450235, -0.00288759356904, 0.999995629903)132.715073878, 138.723839402, -6.98156113197
12given(-0.997434061496, -0.0715910738658, 0.000105408774494), (0.0715910682035, -0.997434065869, -5.655005653E-5), (0.000109186781796, -4.88586258E-5, 0.999999992846)140.354350545, 130.653815116, 11.9736231347
13given(0.996311503815, 0.0858097769591, -0.000263711332551), (-0.0858097076555, 0.996311509769, 0.000263768990788), (0.000285372594145, -0.00024016708752, 0.999999930441)-5.54819360703, 6.05378549729, 14.3702828557
14given(-0.994960359294, -0.100260487181, 0.00131077962765), (0.1002573745, -0.994958976564, -0.00225694766397), (0.00153045462916, -0.00211415813464, 0.999996594016)142.03812082, 128.701127341, 16.8087849354
15given(-0.99827818755, -0.0580825383022, -0.00819017744477), (0.0580290865334, -0.998292945027, 0.00661974505224), (-0.00856068795718, 0.00613307857712, 0.999944548447)141.279248981, 132.141949544, -2.36154230261

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Components

#1: Protein
Isoform Tau-F of Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 45919.871 Da / Num. of mol.: 15
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPT, MAPTL, MTBT1, TAU / Production host: Escherichia coli (E. coli) / References: UniProt: P10636-8
#2: RNA chain RNA (5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')


Mass: 3247.100 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus (mice)

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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: Complex of tau protein and mouse RNA / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Mus (mice)862507
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
Buffer componentConc.: 20 mM / Name: ammonium acetate
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 3900 nm / Nominal defocus min: 760 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 4728

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20_4459refinement
PHENIX1.20_4459refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4CTFFINDCTF correction
11RELIONclassification
12RELION3D reconstruction
13PHENIX1.19.2_4158model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 178.16 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 26061 / Symmetry type: HELICAL
Atomic model buildingB value: 84.4 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: Correlation coefficient
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 81.53 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00614455
ELECTRON MICROSCOPYf_angle_d1.28796160
ELECTRON MICROSCOPYf_chiral_restr0.0653765
ELECTRON MICROSCOPYf_plane_restr0.0083723
ELECTRON MICROSCOPYf_dihedral_angle_d19.38911682
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000520334050936
ens_1d_3AELECTRON MICROSCOPYNCS constraints0.000519478277811
ens_1d_4AELECTRON MICROSCOPYNCS constraints0.000515446304768
ens_1d_5AELECTRON MICROSCOPYNCS constraints0.000518408708794
ens_1d_6AELECTRON MICROSCOPYNCS constraints0.000513707580399
ens_1d_7AELECTRON MICROSCOPYNCS constraints0.000524651312309
ens_1d_8AELECTRON MICROSCOPYNCS constraints0.000520474891744
ens_1d_9AELECTRON MICROSCOPYNCS constraints0.000525193040702
ens_1d_10AELECTRON MICROSCOPYNCS constraints0.000534666894097
ens_1d_11AELECTRON MICROSCOPYNCS constraints0.000526988173319
ens_1d_12AELECTRON MICROSCOPYNCS constraints0.000526024160999
ens_1d_13AELECTRON MICROSCOPYNCS constraints0.000526528491295
ens_1d_14AELECTRON MICROSCOPYNCS constraints0.00051209831371
ens_1d_15AELECTRON MICROSCOPYNCS constraints0.00050847417137
ens_2d_2BELECTRON MICROSCOPYNCS constraints0.000708023862832

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