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- PDB-8a9l: Cryo-EM structure of alpha-synuclein filaments from Parkinson's d... -

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Basic information

Entry
Database: PDB / ID: 8a9l
TitleCryo-EM structure of alpha-synuclein filaments from Parkinson's disease and dementia with Lewy bodies
Components
  • (Unknown fragment) x 2
  • Alpha-synuclein
KeywordsPROTEIN FIBRIL / alpha-synuclein / amyloid / fibril / Parkinson's disease (PD) / Parkinson's disease dementia (PDD) / dementia with Lewy bodies (DLB) / synucleinopathy
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of phospholipase activity / negative regulation of monooxygenase activity / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of transporter activity / mitochondrial membrane organization / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / regulation of norepinephrine uptake / dopamine biosynthetic process / SNARE complex assembly / positive regulation of neurotransmitter secretion / regulation of locomotion / synaptic vesicle priming / positive regulation of inositol phosphate biosynthetic process / regulation of macrophage activation / dopamine uptake involved in synaptic transmission / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / regulation of dopamine secretion / protein kinase inhibitor activity / negative regulation of thrombin-activated receptor signaling pathway / response to type II interferon / cuprous ion binding / mitochondrial ATP synthesis coupled electron transport / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / response to magnesium ion / synaptic vesicle endocytosis / regulation of presynapse assembly / alpha-tubulin binding / negative regulation of serotonin uptake / localization / phospholipid metabolic process / axon terminus / supramolecular fiber organization / inclusion body / cellular response to copper ion / Hsp70 protein binding / cellular response to epinephrine stimulus / excitatory postsynaptic potential / response to interleukin-1 / adult locomotory behavior / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / fatty acid metabolic process / long-term synaptic potentiation / regulation of transmembrane transporter activity / protein tetramerization / phosphoprotein binding / ferrous iron binding / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / negative regulation of protein kinase activity / protein destabilization / phospholipid binding / PKR-mediated signaling / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / tau protein binding / positive regulation of protein serine/threonine kinase activity / receptor internalization / synaptic vesicle membrane / positive regulation of inflammatory response / activation of cysteine-type endopeptidase activity involved in apoptotic process / actin cytoskeleton / positive regulation of peptidyl-serine phosphorylation / cellular response to oxidative stress / actin binding / cell cortex / histone binding / growth cone / postsynapse / chemical synaptic transmission / neuron apoptotic process / negative regulation of neuron apoptotic process / amyloid fibril formation / response to lipopolysaccharide / lysosome / molecular adaptor activity / oxidoreductase activity / transcription cis-regulatory region binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsYang, Y. / Shi, Y. / Schweighauser, M. / Zhang, X.J. / Kotecha, A. / Murzin, A.G. / Garringer, H.J. / Cullinane, P. / Saito, Y. / Foroud, T. ...Yang, Y. / Shi, Y. / Schweighauser, M. / Zhang, X.J. / Kotecha, A. / Murzin, A.G. / Garringer, H.J. / Cullinane, P. / Saito, Y. / Foroud, T. / Warner, T.T. / Hasegawa, K. / Vidal, R. / Murayama, S. / Revesz, T. / Ghetti, B. / Hasegawa, M. / Lashley, T. / Scheres, H.W.S. / Goedert, M.
Funding support United Kingdom, United States, 4items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 to M.G. United Kingdom
Alzheimers Research UK (ARUK) United Kingdom
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Nature / Year: 2022
Title: Structures of α-synuclein filaments from human brains with Lewy pathology.
Authors: Yang Yang / Yang Shi / Manuel Schweighauser / Xianjun Zhang / Abhay Kotecha / Alexey G Murzin / Holly J Garringer / Patrick W Cullinane / Yuko Saito / Tatiana Foroud / Thomas T Warner / ...Authors: Yang Yang / Yang Shi / Manuel Schweighauser / Xianjun Zhang / Abhay Kotecha / Alexey G Murzin / Holly J Garringer / Patrick W Cullinane / Yuko Saito / Tatiana Foroud / Thomas T Warner / Kazuko Hasegawa / Ruben Vidal / Shigeo Murayama / Tamas Revesz / Bernardino Ghetti / Masato Hasegawa / Tammaryn Lashley / Sjors H W Scheres / Michel Goedert /
Abstract: Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathologically, it is characterized by ...Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.
History
DepositionJun 28, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 28, 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
B: Unknown fragment
C: Unknown fragment


Theoretical massNumber of molelcules
Total (without water)15,8883
Polymers15,8883
Non-polymers00
Water1086
1
A: Alpha-synuclein
B: Unknown fragment
C: Unknown fragment

A: Alpha-synuclein
B: Unknown fragment
C: Unknown fragment

A: Alpha-synuclein
B: Unknown fragment
C: Unknown fragment


Theoretical massNumber of molelcules
Total (without water)47,6649
Polymers47,6649
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation2
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(0.999542, 0.030266), (-0.030266, 0.999542), (1)-2.77382, 2.85907, -9.53776
3generate(0.999885, 0.015135), (-0.015135, 0.999885), (1)-1.39772, 1.41907, -4.76888
4generate(0.999885, -0.015135), (0.015135, 0.999885), (1)1.41907, -1.3977, 4.76888
5generate(0.999542, -0.030266), (0.030266, 0.999542), (1)2.85907, -2.77382, 9.53776

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Components

#1: Protein Alpha-synuclein / / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14476.108 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P37840
#2: Protein/peptide Unknown fragment


Mass: 783.958 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Protein/peptide Unknown fragment


Mass: 627.775 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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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: Alpha-synuclein filaments extracted from the human brain with PD, PDD, and DLB
Type: TISSUE / Entity ID: #1-#3 / 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: 1400 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0350 / Classification: refinement
EM software
IDNameVersionCategoryDetails
7Cootmodel fitting
9RELION4initial Euler assignment
12RELION43D reconstruction
19REFMACmodel refinementservalcat
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 0.86 ° / Axial rise/subunit: 4.76 Å / Axial symmetry: C1
3D reconstructionResolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68330 / Symmetry type: HELICAL
RefinementResolution: 2.16→91.6 Å / Cor.coef. Fo:Fc: 0.769 / SU B: 5.034 / SU ML: 0.126 / ESU R: 0.09
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.43496 --
obs0.43496 65106 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 51.001 Å2
Refinement stepCycle: 1 / Total: 576
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0060.012570
ELECTRON MICROSCOPYr_bond_other_d0.0010.016585
ELECTRON MICROSCOPYr_angle_refined_deg1.1551.624769
ELECTRON MICROSCOPYr_angle_other_deg0.4241.5681345
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.82583
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg7.6821089
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0540.2102
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.02642
ELECTRON MICROSCOPYr_gen_planes_other0.0010.0294
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_it4.9054.783341
ELECTRON MICROSCOPYr_mcbond_other4.9024.781341
ELECTRON MICROSCOPYr_mcangle_it7.2987.117421
ELECTRON MICROSCOPYr_mcangle_other7.2947.133422
ELECTRON MICROSCOPYr_scbond_it5.9155.573229
ELECTRON MICROSCOPYr_scbond_other5.9025.586230
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other9.1277.964349
ELECTRON MICROSCOPYr_long_range_B_refined11.79856.69477
ELECTRON MICROSCOPYr_long_range_B_other11.78656.836478
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.16→2.216 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.081 4828 -
obs--100 %

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