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- PDB-7yk8: Cryo-EM structure of dLAG3-alpha-syn fibril -

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Basic information

Entry
Database: PDB / ID: 7yk8
TitleCryo-EM structure of dLAG3-alpha-syn fibril
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / amyloid
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 exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / positive regulation of inositol phosphate biosynthetic process / negative regulation of microtubule polymerization / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / dopamine uptake involved in synaptic transmission / synaptic vesicle transport / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / 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 / kinesin binding / cysteine-type endopeptidase inhibitor activity / synaptic vesicle endocytosis / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / supramolecular fiber organization / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / response to interleukin-1 / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / adult locomotory behavior / SNARE binding / glutathione metabolic process / protein tetramerization / excitatory postsynaptic potential / protein sequestering activity / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / synapse organization / 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: 2.8 Å
AuthorsXu, Q.H. / Xia, W.C. / Tao, Y.Q. / Liu, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Am Chem Soc / Year: 2023
Title: Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy.
Authors: Shengnan Zhang / Juan Li / Qianhui Xu / Wencheng Xia / Youqi Tao / Chaowei Shi / Dan Li / ShengQi Xiang / Cong Liu /
Abstract: Many amyloid fibrils associated with neurodegenerative diseases consist of an ordered fibril core (FC) and disordered terminal regions (TRs). The former represents a stable scaffold, while the latter ...Many amyloid fibrils associated with neurodegenerative diseases consist of an ordered fibril core (FC) and disordered terminal regions (TRs). The former represents a stable scaffold, while the latter is rather active in binding with various partners. Current structural studies mainly focus on the ordered FC since the high flexibility of TRs hinders structural characterization. Here, by combining insensitive nuclei enhanced by polarization transfer-based H-detected solid-state NMR and cryo-EM, we explored the intact structure of an α-syn fibril including both FC and TRs and further studied the conformational dynamics of the fibril upon binding to lymphocyte activation gene 3 (LAG3)─a cell surface receptor that is involved in α-syn fibril transmission in brains. We found that both the N- and C-TRs of α-syn are disordered in free fibrils featuring similar conformation ensembles as those in soluble monomers. While in the presence of the D1 domain of LAG3 (L3D1), the C-TR directly binds to L3D1, meanwhile the N-TR folds into a β-strand and further integrates with the FC, which leads to alteration of the overall fibril structure and surface property. Our work reveals synergistic conformational transition of the intrinsically disordered TRs of α-syn, which sheds light on mechanistic understanding of the essential role of TRs in regulating the structure and pathology of amyloid fibrils.
History
DepositionJul 22, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation / Item: _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
L: Alpha-synuclein
I: Alpha-synuclein
B: Alpha-synuclein
A: Alpha-synuclein
J: Alpha-synuclein
G: Alpha-synuclein
E: Alpha-synuclein
C: Alpha-synuclein
K: Alpha-synuclein
H: Alpha-synuclein
F: Alpha-synuclein
D: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)173,71312
Polymers173,71312
Non-polymers00
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: 14476.108 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli K-12 (bacteria) / Strain (production host): K-12 / 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 dLAG3-alpha-syn fibril / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli K-12 (bacteria)
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: 179.604 ° / Axial rise/subunit: 2.424 Å / Axial symmetry: C1
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82205 / Symmetry type: HELICAL

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