|Entry||Database: PDB / ID: 6h6b|
|Title||Structure of alpha-synuclein fibrils|
|Keywords||PROTEIN FIBRIL / Parkinson's disease / apha-synuclein / fibril / filament|
|Function / homology||Synuclein / Synuclein / Amyloid fiber formation / Alpha-synuclein / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / response to desipramine / regulation of phospholipase activity / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity ...Synuclein / Synuclein / Amyloid fiber formation / Alpha-synuclein / negative regulation of dopamine uptake involved in synaptic transmission / regulation of acyl-CoA biosynthetic process / response to desipramine / regulation of phospholipase activity / negative regulation of norepinephrine uptake / positive regulation of glutathione peroxidase activity / negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / negative regulation of monooxygenase activity / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of glutamate secretion / regulation of reactive oxygen species biosynthetic process / negative regulation of transporter activity / negative regulation of chaperone-mediated autophagy / regulation of norepinephrine uptake / regulation of locomotion / regulation of synaptic vesicle recycling / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / positive regulation of inositol phosphate biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / negative regulation of serotonin uptake / mitochondrial ATP synthesis coupled electron transport / dopamine biosynthetic process / negative regulation of histone acetylation / synaptic vesicle transport / negative regulation of microtubule polymerization / dopamine uptake involved in synaptic transmission / nuclear outer membrane / positive regulation of receptor recycling / regulation of dopamine secretion / dynein complex binding / regulation of macrophage activation / negative regulation of dopamine metabolic process / beta-tubulin binding / supramolecular fiber organization / alpha-tubulin binding / phospholipase binding / kinesin binding / response to magnesium ion / positive regulation of endocytosis / response to interferon-gamma / negative regulation of thrombin-activated receptor signaling pathway / cellular response to fibroblast growth factor stimulus / synaptic vesicle endocytosis / cuprous ion binding / regulation of presynapse assembly / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / behavioral response to cocaine / excitatory postsynaptic potential / response to interleukin-1 / inclusion body / regulation of transmembrane transporter activity / synapse organization / Hsp70 protein binding / microglial cell activation / adult locomotory behavior / phospholipid metabolic process / cellular response to epinephrine stimulus / long-term synaptic potentiation / tau protein binding / positive regulation of protein serine/threonine kinase activity / fatty acid metabolic process / synaptic vesicle membrane / rough endoplasmic reticulum / negative regulation of protein phosphorylation / ferrous iron binding / receptor internalization / positive regulation of release of sequestered calcium ion into cytosol / regulation of long-term neuronal synaptic plasticity / protein destabilization / cellular response to copper ion / negative regulation of neuron death / phosphoprotein binding / positive regulation of inflammatory response / terminal bouton / phospholipid binding / mitochondrial intermembrane space / postsynapse / actin cytoskeleton / activation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron death / cell cortex / cellular response to oxidative stress / growth cone / actin binding / mitochondrial inner membrane / histone binding / transcription regulatory region DNA binding / protein N-terminus binding / positive regulation of peptidyl-serine phosphorylation / ribosome|
Function and homology information
|Specimen source||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / helical reconstruction / cryo EM / 3.4 Å resolution|
|Authors||Guerrero-Ferreira, R. / Taylor, N.M.I. / Mona, D. / Ringler, P. / Lauer, M.E. / Riek, R. / Britschgi, M. / Stahlberg, H.|
|Citation||Journal: Elife / Year: 2018|
Title: Cryo-EM structure of alpha-synuclein fibrils.
Authors: Ricardo Guerrero-Ferreira / Nicholas Mi Taylor / Daniel Mona / Philippe Ringler / Matthias E Lauer / Roland Riek / Markus Britschgi / Henning Stahlberg
Abstract: Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in ...Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.
SummaryFull reportAbout validation report
|Date||Deposition: Jul 26, 2018 / Release: Aug 8, 2018|
|Structure viewer||Molecule: |
Downloads & links
Mass: 12242.873 Da / Num. of mol.: 10 / Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Plasmid name: pET21
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P37840
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / Reconstruction method: helical reconstruction|
|Component||Name: Alpha-synuclein fibrils / Type: COMPLEX / Details: Residues 1-121 / Entity ID: 1 / Source: RECOMBINANT|
|Molecular weight||Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)|
|Buffer solution||pH: 7.3|
|Specimen||Conc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: COPPER / Grid mesh size: 300 / Grid type: Quantifoil R2/2|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 kelvins|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 100 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|EM imaging optics||Energyfilter name: GIF Quantum LS|
|Image scans||Movie frames/image: 50 / Used frames/image: 2-50|
|Software||Name: PHENIX / Version: 1.13_2998: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Helical symmerty||Angular rotation/subunit: 179.5 deg. / Axial rise/subunit: 2.45 Å / Axial symmetry: C1|
|Particle selection||Details: Segments extracted from 792 manually picked fibrils|
Number of particles selected: 18860
|3D reconstruction||Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 13390 / Symmetry type: HELICAL|
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