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- PDB-8qn6: Amyloid-beta 40 type 2 filament from the leptomeninges of individ... -

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Basic information

Entry
Database: PDB / ID: 8qn6
TitleAmyloid-beta 40 type 2 filament from the leptomeninges of individual with Alzheimer's disease and cerebral amyloid angiopathy
ComponentsAmyloid-beta A4 protein
KeywordsPROTEIN FIBRIL / amyloid-beta / amyloid / filaments / quadruplet / Abeta40 / human brain / cryo-EM / Alzheimer's disease / cerebral amyloid angiopathy
Function / homology
Function and homology information


Golgi-associated vesicle / clathrin-coated pit / heparin binding / growth cone / perikaryon / early endosome / Golgi apparatus / cell surface / endoplasmic reticulum / extracellular region / nucleus
Similarity search - Function
Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / Amyloidogenic glycoprotein, extracellular ...Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / amyloid A4 / Amyloidogenic glycoprotein / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta A4 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsYang, Y. / Murzin, A.S. / Peak-Chew, S.Y. / Franco, C. / Newell, K.L. / Ghetti, B. / Goedert, M. / Scheres, S.H.W.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
Wellcome Trust United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC) United Kingdom
CitationJournal: Acta Neuropathol Commun / Year: 2023
Title: Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy.
Authors: Yang Yang / Alexey G Murzin / Sew Peak-Chew / Catarina Franco / Holly J Garringer / Kathy L Newell / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
Abstract: We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement ...We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.
History
DepositionSep 25, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Structure summary / Category: entity_name_com / struct / Item: _struct.title
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: em_3d_fitting_list / em_author_list / pdbx_initial_refinement_model
Item: _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.pdb_entry_id ..._em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.pdb_entry_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_author_list.author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein


Theoretical massNumber of molelcules
Total (without water)8,6722
Polymers8,6722
Non-polymers00
Water0
1
F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein
x 6
F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein

F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein

F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein

F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein

F: Amyloid-beta A4 protein
A: Amyloid-beta A4 protein


Theoretical massNumber of molelcules
Total (without water)95,38922
Polymers95,38922
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation9
identity operation1_555x,y,z2
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.999905, -0.013772), (0.013772, 0.999905), (1)1.6507, -1.6282, 4.8727
3generate(-0.999905, 0.013772), (-0.013772, -0.999905), (1)236.4293, 239.7082, 4.8727
4generate(0.999905, 0.013772), (-0.013772, 0.999905), (1)-1.6282, 1.6507, -4.8727
5generate(-1), (-1), (1)238.08, 238.08

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Components

#1: Protein/peptide Amyloid-beta A4 protein / Amyloid-beta 40 protein


Mass: 4335.852 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: B4DM00

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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: Amyloid-beta 40Amyloid beta / Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2EPUimage acquisition
4RELIONCTF correction
7Cootmodel fitting
9RELIONinitial Euler assignment
10RELIONfinal Euler assignment
11RELIONclassification
12RELION3D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.78 ° / Axial rise/subunit: 4.87 Å / Axial symmetry: C2
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 81140 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 7Q4B

7q4b


Accession code: 7Q4B / Source name: PDB / Type: experimental model
RefinementResolution: 2.4→142.85 Å / Cor.coef. Fo:Fc: 0.768 / SU B: 5.681 / SU ML: 0.127 / ESU R: 0.086
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.43367 --
obs0.43367 88560 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 64.292 Å2
Refinement stepCycle: 1 / Total: 582
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.012594
ELECTRON MICROSCOPYr_bond_other_d0.0010.016536
ELECTRON MICROSCOPYr_angle_refined_deg1.0791.635794
ELECTRON MICROSCOPYr_angle_other_deg0.531.6031232
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.263574
ELECTRON MICROSCOPYr_dihedral_angle_2_deg1.53752
ELECTRON MICROSCOPYr_dihedral_angle_3_deg8.9911094
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0470.280
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.02706
ELECTRON MICROSCOPYr_gen_planes_other0.0020.02142
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it4.5745.949302
ELECTRON MICROSCOPYr_mcbond_other4.5445.943302
ELECTRON MICROSCOPYr_mcangle_it7.05410.689374
ELECTRON MICROSCOPYr_mcangle_other7.07110.695375
ELECTRON MICROSCOPYr_scbond_it6.2597.099292
ELECTRON MICROSCOPYr_scbond_other6.2497.105293
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other10.48312.576421
ELECTRON MICROSCOPYr_long_range_B_refined14.99157.63534
ELECTRON MICROSCOPYr_long_range_B_other15.00557.66535
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.008 6575 -
obs--100 %

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