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- EMDB-20328: Cryo-EM structure of alpha-synuclein H50Q Narrow Fibril -

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Basic information

Entry
Database: EMDB / ID: EMD-20328
TitleCryo-EM structure of alpha-synuclein H50Q Narrow Fibril
Map data
Sample
  • Organelle or cellular component: Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Narrow Fibril polymorph
    • Protein or peptide: Alpha-synuclein
KeywordsAlpha-synuclein / amyloid / H50Q / hereditary mutation / fibril / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / dopamine biosynthetic process / dopamine uptake involved in synaptic transmission / negative regulation of dopamine metabolic process / response to iron(II) ion / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of microtubule polymerization / negative regulation of thrombin-activated receptor signaling pathway / synaptic vesicle priming / synaptic vesicle transport / Lewy body / regulation of norepinephrine uptake / synaptic vesicle exocytosis / transporter regulator activity / protein kinase inhibitor activity / positive regulation of inositol phosphate biosynthetic process / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / regulation of dopamine secretion / response to magnesium ion / positive regulation of endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / kinesin binding / regulation of presynapse assembly / alpha-tubulin binding / synaptic vesicle endocytosis / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / supramolecular fiber organization / response to type II interferon / cellular response to epinephrine stimulus / inclusion body / response to interleukin-1 / Hsp70 protein binding / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / axon terminus / enzyme inhibitor activity / glutathione metabolic process / SNARE binding / protein tetramerization / regulation of microtubule cytoskeleton organization / phosphoprotein binding / receptor internalization / protein destabilization / microglial cell activation / tubulin binding / ferrous iron binding / protein sequestering activity / phospholipid binding / synapse organization / PKR-mediated signaling / tau protein binding / enzyme activator activity / positive regulation of inflammatory response / actin cytoskeleton / terminal bouton / synaptic vesicle membrane / negative regulation of neuron apoptotic process / actin binding / response to lipopolysaccharide / growth cone / cellular response to oxidative stress / histone binding / cell cortex / amyloid fibril formation / microtubule binding / oxidoreductase activity / mitochondrial outer membrane / lysosome / transcription cis-regulatory region binding / mitochondrial inner membrane / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / neuronal cell body / lipid binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBoyer DR / Li B
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG054022 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG061847 United States
Department of Energy (DOE, United States)DE-FC02-02ER63421 United States
CitationJournal: Nat Struct Mol Biol / Year: 2019
Title: Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs.
Authors: David R Boyer / Binsen Li / Chuanqi Sun / Weijia Fan / Michael R Sawaya / Lin Jiang / David S Eisenberg /
Abstract: Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein ...Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions. Seeing the changes to the structures of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two previously unobserved polymorphs of α-synuclein: narrow and wide fibrils, formed from either one or two protofilaments, respectively. These structures recapitulate conserved features of the wild-type fold but reveal new structural elements, including a previously unobserved hydrogen-bond network and surprising new protofilament arrangements. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells and greater cytotoxicity that we observe for H50Q compared to wild-type α-synuclein.
History
DepositionJun 20, 2019-
Header (metadata) releaseAug 21, 2019-
Map releaseNov 27, 2019-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6peo
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6peo
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20328.png

Downloads & links

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Map

FileDownload / File: emd_20328.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.07 Å/pix.
x 128 pix.
= 136.32 Å		1.07 Å/pix.
x 128 pix.
= 136.32 Å		1.07 Å/pix.
x 128 pix.
= 136.32 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.065 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0 / Movie #1: 2
Minimum - Maximum-9.151801000000001 - 10.463862000000001
Average (Standard dev.)-0.000000000025389 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-64-64-64
Dimensions128128128
Spacing128128128
CellA=B=C: 136.32 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0651.0651.065
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z136.320136.320136.320
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S321
start NC/NR/NS-64-64-64
NC/NR/NS128128128
D min/max/mean-9.15210.464-0.000

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Supplemental data

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Sample components

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Entire : Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Na...

EntireName: Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Narrow Fibril polymorph
Components
  • Organelle or cellular component: Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Narrow Fibril polymorph
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Na...

SupramoleculeName: Alpha-synuclein amyloid fibril with H50Q hereditary mutation - Narrow Fibril polymorph
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.466091 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVQ GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 26.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.81 Å
Applied symmetry - Helical parameters - Δ&Phi: 0.97 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2) / Number images used: 30133
CTF correctionSoftware - Name: CTFFIND (ver. 4.1.8) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2)
FSC plot (resolution estimation)

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