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- PDB-8fpt: STRUCTURE OF ALPHA-SYNUCLEIN FIBRILS DERIVED FROM HUMAN LEWY BODY... -

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Basic information

Entry
Database: PDB / ID: 8fpt
TitleSTRUCTURE OF ALPHA-SYNUCLEIN FIBRILS DERIVED FROM HUMAN LEWY BODY DEMENTIA TISSUE
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / AMYLOID / LEWY BODY DEMENTIA / POLYMORPHISM / PARKINSON / STRUCTURAL PROTEIN
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / : / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / SNARE complex assembly / regulation of norepinephrine uptake / response to iron(II) ion / positive regulation of neurotransmitter secretion / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / negative regulation of dopamine metabolic process / regulation of macrophage activation / transporter regulator activity / negative regulation of microtubule polymerization / synaptic vesicle transport / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / mitochondrial ATP synthesis coupled electron transport / regulation of dopamine secretion / dynein complex binding / positive regulation of receptor recycling / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of endocytosis / positive regulation of exocytosis / synaptic vesicle exocytosis / kinesin binding / enzyme inhibitor activity / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / response to type II interferon / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / behavioral response to cocaine / phospholipase binding / supramolecular fiber organization / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / axon terminus / Hsp70 protein binding / cellular response to epinephrine stimulus / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / phosphoprotein binding / protein tetramerization / microglial cell activation / fatty acid metabolic process / ferrous iron binding / regulation of long-term neuronal synaptic plasticity / synapse organization / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / molecular adaptor activity / chemical synaptic transmission / amyloid fibril formation / mitochondrial outer membrane / negative regulation of neuron apoptotic process / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodSOLID-STATE NMR / simulated annealing
AuthorsBarclay, A.M. / Dhavale, D.D. / Borcik, C.G. / Rau, M.J. / Basore, K. / Milchberg, M.H. / Warmuth, O.A. / Kotzbauer, P.T. / Rienstra, C.M. / Schwieters, C.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2024
Title: Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue.
Authors: Dhavale, D.D. / Barclay, A.M. / Borcik, C.G. / Basore, K. / Berthold, D.A. / Gordon, I.R. / Liu, J. / Milchberg, M.H. / O'Shea, J.Y. / Rau, M.J. / Smith, Z. / Sen, S. / Summers, B. / Smith, ...Authors: Dhavale, D.D. / Barclay, A.M. / Borcik, C.G. / Basore, K. / Berthold, D.A. / Gordon, I.R. / Liu, J. / Milchberg, M.H. / O'Shea, J.Y. / Rau, M.J. / Smith, Z. / Sen, S. / Summers, B. / Smith, J. / Warmuth, O.A. / Perrin, R.J. / Perlmutter, J.S. / Chen, Q. / Fitzpatrick, J.A.J. / Schwieters, C.D. / Tajkhorshid, E. / Rienstra, C.M. / Kotzbauer, P.T.
History
DepositionJan 5, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI
Revision 1.2Dec 11, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_nmr_spectrometer
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.year / _pdbx_nmr_spectrometer.manufacturer

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein
G: Alpha-synuclein
H: Alpha-synuclein
I: Alpha-synuclein
J: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)144,76110
Polymers144,76110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: NMR Distance Restraints
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 256structures with the lowest energy
RepresentativeModel #1lowest energy

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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.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Plasmid: PET28A-AS / Production host: Escherichia coli BL21(DE3) (bacteria) / Tissue (production host): HUMAN BRAIN TISSUE / References: UniProt: P37840
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: SOLID-STATE NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D CC DARR
1301isotropic12D CC SPC7
1291isotropic13D NCACX DARR
1281isotropic13D NCOCX DARR
1271isotropic13D CANCO
1261isotropic22D CC DARR
1251isotropic22D NCA
1241isotropic22D NCO
1231isotropic23D NCACX DARR
1221isotropic23D NCOCX DARR
1211isotropic23D NCOCA SPC5
1201isotropic23D CANCO
1191isotropic12D CC PAR
1181isotropic13D CCC RFDR THEN PAR
1171isotropic23D NCACX PAR
1161isotropic21D C FSREDOR
1152isotropic13D CANH
1142isotropic13D CONH
1132isotropic13D CA[CO]NH RFDR
1122isotropic13D CO[CA]NH RFDR
1112isotropic13D CAN[H]H RFDR
1102isotropic13D CA[HH]NH RFDR
192isotropic13D N[HH]NH RFDR
182isotropic14D HN[HH]NH RFDR
172isotropic12D CACO CTUC-COSY
162isotropic22D CC FPRFDR
153isotropic22D CC DARR
143isotropic22D NCA
133isotropic22D NCO

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solid166 % [U-100% 13C; U-100% 15N] ALPHA-SYNUCLEIN, 34% H2OREHYDRATED FIBRILuCN34% H2O
solid266 % [U-100% 2H; U-100% 13C; U-100% 15N] ALPHA-SYNUCLEIN, 34% H2O, BACK-EXCHANGED IN 99.8% D2OuDCN34% H2O, BACK-EXCHANGED IN 99.8% D2O
solid320 % [U-25% 2-13C GLYCEROL; U-100% 15N] labelled ALPHA-SYNUCLEIN, 80 % ALPHA-SYNUCLEIN, H2ODilutedH2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
66 %ALPHA-SYNUCLEIN[U-100% 13C; U-100% 15N]1
66 %ALPHA-SYNUCLEIN[U-100% 2H; U-100% 13C; U-100% 15N]2
20 %labelled ALPHA-SYNUCLEIN[U-25% 2-13C GLYCEROL; U-100% 15N]3
80 %ALPHA-SYNUCLEINnatural abundance3
Sample conditionsIonic strength: 100 mM NACL mM / Label: SAMPLE_COND / pH: 7.6 / Pressure: AMBIENT / Temperature: 273 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Varian VNMRSVarianVNMRS7501
Varian VNMRSVarianVNMRS5002

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Processing

NMR software
NameDeveloperClassification
X-PLOR NIHSchwieters, Kuszewski, Tjandra and Clorestructure calculation
X-PLOR NIHSchwieters, Kuszewski, Tjandra and Clorerefinement
NMRFAM-SPARKYLEE, TONELLI and MARKLEYchemical shift assignment
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxdata analysis
NMRFAM-SPARKYLEE, TONELLI, and MARKLEYpeak picking
RefinementMethod: simulated annealing / Software ordinal: 2
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 256 / Conformers submitted total number: 10

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