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- PDB-8a7q: beta-2-microglobulin V27M amyloid fibril form 4PF -

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Basic information

Entry
Database: PDB / ID: 8a7q
Titlebeta-2-microglobulin V27M amyloid fibril form 4PF
ComponentsBeta-2-microglobulinBeta-2 microglobulin
KeywordsPROTEIN FIBRIL / Amyloid / fibril / helical / cross-beta / dialysis-related amyloidosis / polymorph / b2m
Function / homology
Function and homology information


positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / early endosome lumen / positive regulation of receptor binding / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent ...positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / early endosome lumen / positive regulation of receptor binding / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / negative regulation of forebrain neuron differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / response to molecule of bacterial origin / regulation of erythrocyte differentiation / regulation of iron ion transport / MHC class I peptide loading complex / HFE-transferrin receptor complex / T cell mediated cytotoxicity / cellular response to iron ion / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / positive regulation of T cell mediated cytotoxicity / peptide antigen assembly with MHC class II protein complex / negative regulation of neurogenesis / MHC class II protein complex / positive regulation of receptor-mediated endocytosis / cellular response to nicotine / recycling endosome membrane / phagocytic vesicle membrane / specific granule lumen / peptide antigen binding / positive regulation of cellular senescence / antigen processing and presentation of exogenous peptide antigen via MHC class II / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Interferon gamma signaling / positive regulation of immune response / negative regulation of epithelial cell proliferation / Modulation by Mtb of host immune system / positive regulation of T cell activation / sensory perception of smell / negative regulation of neuron projection development / tertiary granule lumen / DAP12 signaling / MHC class II protein complex binding / late endosome membrane / T cell differentiation in thymus / positive regulation of protein binding / ER-Phagosome pathway / iron ion transport / protein refolding / early endosome membrane / protein homotetramerization / intracellular iron ion homeostasis / amyloid fibril formation / learning or memory / Amyloid fiber formation / lysosomal membrane / endoplasmic reticulum lumen / external side of plasma membrane / Golgi membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / Golgi apparatus / endoplasmic reticulum / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Beta-2-Microglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWilkinson, M. / Gallardo, R. / Radford, S.E. / Ranson, N.A.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Medical Research Council (MRC, United Kingdom) United Kingdom
Royal Society United Kingdom
CitationJournal: Nat Commun / Year: 2023
Title: Disease-relevant β-microglobulin variants share a common amyloid fold.
Authors: Martin Wilkinson / Rodrigo U Gallardo / Roberto Maya Martinez / Nicolas Guthertz / Masatomo So / Liam D Aubrey / Sheena E Radford / Neil A Ranson /
Abstract: β-microglobulin (βm) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of βm result in ...β-microglobulin (βm) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils in the joints, causing the disorder dialysis-related amyloidosis (DRA). Point mutations of βm result in diseases with distinct pathologies. βm-D76N causes a rare systemic amyloidosis with protein deposited in the viscera in the absence of renal failure, whilst βm-V27M is associated with renal failure, with amyloid deposits forming predominantly in the tongue. Here we use cryoEM to determine the structures of fibrils formed from these variants under identical conditions in vitro. We show that each fibril sample is polymorphic, with diversity arising from a 'lego-like' assembly of a common amyloid building block. These results suggest a 'many sequences, one amyloid fold' paradigm in contrast with the recently reported 'one sequence, many amyloid folds' behaviour of intrinsically disordered proteins such as tau and Aβ.
History
DepositionJun 21, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-2-microglobulin
B: Beta-2-microglobulin
C: Beta-2-microglobulin
D: Beta-2-microglobulin
E: Beta-2-microglobulin
F: Beta-2-microglobulin
G: Beta-2-microglobulin
H: Beta-2-microglobulin
I: Beta-2-microglobulin
J: Beta-2-microglobulin
K: Beta-2-microglobulin
L: Beta-2-microglobulin


Theoretical massNumber of molelcules
Total (without water)141,36312
Polymers141,36312
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Beta-2-microglobulin / Beta-2 microglobulin


Mass: 11780.226 Da / Num. of mol.: 12 / Mutation: V27M
Source method: isolated from a genetically manipulated source
Details: Natural b2m variant V27M / Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Variant: V27M / Plasmid: pINK / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P61769

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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: Amyloid fibril polymorph 2PFa of the beta-2-microglobulin deltaN6 variant.
Type: COMPLEX
Details: Recombinantly expressed and fibrillated in vitro at pH 6.2
Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21 / Plasmid: pINK
Buffer solutionpH: 6.2
Buffer component
IDConc.NameFormulaBuffer-ID
1115 mMsodium chlorideNaClSodium chloride1
225 mMsodium phosphate1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Fibrillation conditions: 20 uM monomeric b2m-V27M at 37C with shaking at 600 rpm for 3-4 weeks
Specimen supportDetails: The grid was plasma cleaned prior to 2x application of graphene oxide-DDM mixture, then grid was used immediately for sample application and vitrification
Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K / Details: 6s blot

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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 FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 43 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4079
Details: 1442 raw EER frames were collected per image and combined into 40 fractions for processing
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
9RELION4initial Euler assignment
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIX1.17model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.73 ° / Axial rise/subunit: 4.85 Å / Axial symmetry: C2
Particle selectionNum. of particles selected: 229692
Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4732 / Symmetry type: HELICAL
Atomic model buildingB value: 44 / Protocol: AB INITIO MODEL / Space: REAL

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