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- PDB-9hgs: In vitro grown G14R Alpha-Synuclein Fibrils -

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Basic information

Entry
Database: PDB / ID: 9hgs
TitleIn vitro grown G14R Alpha-Synuclein Fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Alpha-Synuclein / G14R Mutation / Fibrils / Cryo-EM / Protein Aggregation / Amyloid Structure
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 / 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 / regulation of locomotion / negative regulation of microtubule polymerization / synaptic vesicle transport / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / mitochondrial ATP synthesis coupled electron transport / positive regulation of receptor recycling / dynein complex binding / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / synaptic vesicle endocytosis / kinesin binding / 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 / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to fibroblast growth factor stimulus / phospholipid metabolic process / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / 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 / protein tetramerization / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / synapse organization / regulation of long-term neuronal synaptic plasticity / phospholipid binding / receptor internalization / protein destabilization / tau protein binding / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / 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 / amyloid fibril formation / chemical synaptic transmission / negative regulation of neuron apoptotic process / molecular adaptor activity / mitochondrial outer membrane / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsSicking, K. / Fernandez-Busnadiego, R.
Funding support Germany, United States, 5items
OrganizationGrant numberCountry
German Research Foundation (DFG)EXC 2067/1-390729940 Germany
German Research Foundation (DFG)SFB1286 (B8) Germany
German Research Foundation (DFG)SFB1286 (A12) Germany
German Research Foundation (DFG)448415290 Germany
Michael J. Fox FoundationASAP-000282 United States
Citation
Journal: medRxiv / Year: 2025
Title: A novel alpha-synuclein K58N missense variant in a patient with Parkinson's disease.
Authors: Mohammed Al-Azzani / Sandrina Weber / Nagendran Ramalingam / Maria Ramón / Liana Shvachiy / Gonçalo Mestre / Michael Zech / Kevin Sicking / Alain Ibáñez de Opakua / Vidyashree Jayanthi / ...Authors: Mohammed Al-Azzani / Sandrina Weber / Nagendran Ramalingam / Maria Ramón / Liana Shvachiy / Gonçalo Mestre / Michael Zech / Kevin Sicking / Alain Ibáñez de Opakua / Vidyashree Jayanthi / Leslie Amaral / Aishwarya Agarwal / Aswathy Chandran / Susana R Chaves / Juliane Winkelmann / Claudia Trenkwalder / Maike Schwager / Silke Pauli / Ulf Dettmer / Claudio O Fernández / Janin Lautenschläger / Markus Zweckstetter / Ruben Fernandez Busnadiego / Brit Mollenhauer / Tiago Fleming Outeiro /
Abstract: Mutations and multiplications in the SNCA , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report the identification of a novel missense mutation ...Mutations and multiplications in the SNCA , encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson's disease (PD). We report the identification of a novel missense mutation (NM_000345.4, cDNA 174G>C; protein K58N) in a PD patient using whole exome sequencing, and describe comprehensive molecular and cellular analysss of the effects of this novel mutation. The patient exhibited typical sporadic PD with early onset and a benign disease course. Biophysical studies revealed that the K58N substitution causes local structural effects, disrupts binding to membranes, and enhances aSyn in vitro aggregation. K58N aSyn produces fewer inclusions per cell, and fails to undergo condensate formation. The mutation increases the cytoplasmic distribution of the protein, and has minimal effect on the dynamic reversibility of serine-129 phosphorylation. In total, the identification of this novel mutation advances our understanding of aSyn biology and pathobiology.
#1: Journal: medRxiv / Year: 2025
Title: A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features.
Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / ...Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / Aishwarya Agarwal / Susana R Chaves / Claudio O Fernández / Ulf Dettmer / Janin Lautenschläger / Markus Zweckstetter / Ruben Fernandez Busnadiego / Alexander Zimprich / Tiago Fleming Outeiro /
Abstract: BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for ...BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD.
AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological ...AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays.
RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant ...RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation.
SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and ...SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies.
History
DepositionNov 20, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jan 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.1Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / Item: _em_admin.last_update
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.2Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)14,5761
Polymers14,5761
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
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: 14576.251 Da / Num. of mol.: 1
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
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Alpha-Synuclein G14R / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 14.46 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128762 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001526
ELECTRON MICROSCOPYf_angle_d0.345706
ELECTRON MICROSCOPYf_dihedral_angle_d3.9874
ELECTRON MICROSCOPYf_chiral_restr0.04792
ELECTRON MICROSCOPYf_plane_restr0.00187

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