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- PDB-8jey: Cryo-EM structure of alpha-synuclein pS87 fibril -

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Basic information

Entry
Database: PDB / ID: 8jey
TitleCryo-EM structure of alpha-synuclein pS87 fibril
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid
Function / homology
Function and homology information


regulation of phospholipase activity / : / 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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process ...regulation of phospholipase activity / : / 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 / 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 synaptic vesicle recycling / 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 / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / regulation of locomotion / synaptic vesicle priming / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle transport / dynein complex binding / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of endocytosis / synaptic vesicle exocytosis / positive regulation of exocytosis / response to magnesium ion / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / kinesin binding / synaptic vesicle endocytosis / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / alpha-tubulin binding / inclusion body / supramolecular fiber organization / phospholipid metabolic process / cellular response to copper ion / cellular response to epinephrine stimulus / axon terminus / Hsp70 protein binding / response to interleukin-1 / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / excitatory postsynaptic potential / fatty acid metabolic process / positive regulation of protein serine/threonine kinase activity / phosphoprotein binding / negative regulation of protein kinase activity / protein tetramerization / long-term synaptic potentiation / regulation of transmembrane transporter activity / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / positive regulation of peptidyl-serine phosphorylation / protein destabilization / PKR-mediated signaling / tau protein binding / receptor internalization / phospholipid binding / synaptic vesicle membrane / positive regulation of inflammatory response / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / chemical synaptic transmission / neuron apoptotic process / molecular adaptor activity / response to lipopolysaccharide / negative regulation of neuron apoptotic process / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / copper ion binding / response to xenobiotic stimulus
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsXia, W.C. / Sun, Y.P. / Liu, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.
Authors: Jinjian Hu / Wencheng Xia / Shuyi Zeng / Yeh-Jun Lim / Youqi Tao / Yunpeng Sun / Lang Zhao / Haosen Wang / Weidong Le / Dan Li / Shengnan Zhang / Cong Liu / Yan-Mei Li /
Abstract: α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications ...α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.
History
DepositionMay 16, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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


Theoretical massNumber of molelcules
Total (without water)86,8576
Polymers86,8576
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli (E. coli) / References: UniProt: P37840

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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: Cryo-EM structure of alpha-synuclein pS87 fibril / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
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 FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -179.72 ° / Axial rise/subunit: 2.41 Å / Axial symmetry: C1
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61047 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033072
ELECTRON MICROSCOPYf_angle_d0.654110
ELECTRON MICROSCOPYf_dihedral_angle_d13.6031860
ELECTRON MICROSCOPYf_chiral_restr0.048510
ELECTRON MICROSCOPYf_plane_restr0.002510

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