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- PDB-8gf7: Cryo-EM structure of serine 87 O-GlcNAc-modified alpha-synuclein ... -

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Basic information

Entry
Database: PDB / ID: 8gf7
TitleCryo-EM structure of serine 87 O-GlcNAc-modified alpha-synuclein fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / alpha-synuclein / O-GlcNAc / amyloid / fibril / posttranslational modification
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 / regulation of synaptic vesicle recycling ...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 / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / negative regulation of thrombin-activated receptor signaling pathway / SNARE complex assembly / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / Lewy body / regulation of locomotion / negative regulation of microtubule polymerization / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / synaptic vesicle transport / protein kinase inhibitor activity / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / positive regulation of exocytosis / cuprous ion binding / nuclear outer membrane / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / synaptic vesicle endocytosis / kinesin binding / regulation of presynapse assembly / cysteine-type endopeptidase inhibitor activity / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / axon terminus / enzyme inhibitor activity / response to interleukin-1 / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / excitatory postsynaptic potential / protein tetramerization / protein sequestering activity / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / synapse organization / PKR-mediated signaling / regulation of long-term neuronal synaptic plasticity / receptor internalization / phospholipid binding / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.8 Å
AuthorsBalana, J.A. / Nguyen, A.B. / Saelices, L. / Pratt, R.M.
Funding support United States, 7items
OrganizationGrant numberCountry
Michael J. Fox FoundationMJFF-008121 United States
National Institutes of Health/Office of the DirectorOD020103-01 United States
National Institutes of Health/Office of the DirectorOD021685-01A1 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG062418 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM114537 United States
Department of Energy (DOE, United States)DE-AC02-76SF00515 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP170644 United States
CitationJournal: Nat Chem Biol / Year: 2024
Title: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.
Authors: Aaron T Balana / Anne-Laure Mahul-Mellier / Binh A Nguyen / Mian Horvath / Afraah Javed / Eldon R Hard / Yllza Jasiqi / Preeti Singh / Shumaila Afrin / Rose Pedretti / Virender Singh / ...Authors: Aaron T Balana / Anne-Laure Mahul-Mellier / Binh A Nguyen / Mian Horvath / Afraah Javed / Eldon R Hard / Yllza Jasiqi / Preeti Singh / Shumaila Afrin / Rose Pedretti / Virender Singh / Virginia M-Y Lee / Kelvin C Luk / Lorena Saelices / Hilal A Lashuel / Matthew R Pratt /
Abstract: Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, ...Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.
History
DepositionMar 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 15, 2024Group: 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
Revision 1.3Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,01312
Polymers52,6866
Non-polymers1,3276
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 8781.005 Da / Num. of mol.: 6 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P37840
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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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 fibrils / Type: COMPLEX / Details: The protein is semi-synthesized. / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: normal PBS
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: 2200 nm / Nominal defocus min: 800 nm
Image recordingAverage exposure time: 3.6 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 7270 / Details: 3 shots per hole

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
1EMAN22.31particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
7Coot0.9.8.1model fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
12RELION3.13D reconstruction
13PHENIX20.1model refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -0.7 ° / Axial rise/subunit: 4.926 Å / Axial symmetry: C1
3D reconstructionResolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 22042 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 6A6B

6a6b


Accession code: 6A6B / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0023702
ELECTRON MICROSCOPYf_angle_d0.5664980
ELECTRON MICROSCOPYf_dihedral_angle_d11.0731290
ELECTRON MICROSCOPYf_chiral_restr0.052636
ELECTRON MICROSCOPYf_plane_restr0.001624

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