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- EMDB-12570: AL amyloid fibril from a lambda 1 light chain -

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Basic information

Entry
Database: EMDB / ID: EMD-12570
TitleAL amyloid fibril from a lambda 1 light chain
Map data
Sample
  • Complex: Amyloid fibril of an antibody lambda 1 immunoglobulin light chain
    • Protein or peptide: Amyloid lambda1 light chain
Biological speciesHomo sapiens (human) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsKarimi Farsijani S / Radamaker L / Fandrich M
Funding support Germany, 1 items
OrganizationGrant numberCountry
German Research Foundation (DFG)FOR2969 Germany
CitationJournal: Nat Commun / Year: 2021
Title: Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM.
Authors: Lynn Radamaker / Sara Karimi-Farsijani / Giada Andreotti / Julian Baur / Matthias Neumann / Sarah Schreiner / Natalie Berghaus / Raoul Motika / Christian Haupt / Paul Walther / Volker ...Authors: Lynn Radamaker / Sara Karimi-Farsijani / Giada Andreotti / Julian Baur / Matthias Neumann / Sarah Schreiner / Natalie Berghaus / Raoul Motika / Christian Haupt / Paul Walther / Volker Schmidt / Stefanie Huhn / Ute Hegenbart / Stefan O Schönland / Sebastian Wiese / Clarissa Read / Matthias Schmidt / Marcus Fändrich /
Abstract: Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational ...Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.
History
DepositionMar 8, 2021-
Header (metadata) releaseNov 24, 2021-
Map releaseNov 24, 2021-
UpdateNov 24, 2021-
Current statusNov 24, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7nsl
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7nsl
  • Imaged by Jmol
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12570.png

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Map

FileDownload / File: emd_12570.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 12.0 / Movie #1: 12
Minimum - Maximum-24.973225 - 49.14803
Average (Standard dev.)-1.8761297e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 270.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z260260260
origin x/y/z0.0000.0000.000
length x/y/z270.400270.400270.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ260260260
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS260260260
D min/max/mean-24.97349.148-0.000

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Supplemental data

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Half map: #2

Fileemd_12570_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_12570_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid fibril of an antibody lambda 1 immunoglobulin light chain

EntireName: Amyloid fibril of an antibody lambda 1 immunoglobulin light chain
Components
  • Complex: Amyloid fibril of an antibody lambda 1 immunoglobulin light chain
    • Protein or peptide: Amyloid lambda1 light chain

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Supramolecule #1: Amyloid fibril of an antibody lambda 1 immunoglobulin light chain

SupramoleculeName: Amyloid fibril of an antibody lambda 1 immunoglobulin light chain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Extracted fibrils from the explanted heart of a patient suffering from systemic AL amyloidosis
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart muscle

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Macromolecule #1: Amyloid lambda1 light chain

MacromoleculeName: Amyloid lambda1 light chain / type: protein_or_peptide / ID: 1 / Number of copies: 7 / Enantiomer: LEVO
Source (natural)Organism: Human (human) / Organ: Heart / Tissue: Heart muscle tissue
Molecular weightTheoretical: 12.122354 KDa
SequenceString:
QSVLTQPPSV SAAPGQNVTI SCSGSSSNIG NNYVSWYQQL PGTAPKLLIY ETDKRPSGIP DRFSGSKSGT SATLGITGLQ TADEADYYC GTWESSLLAG VFGGGTKLTV LGQPKAAPS

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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 / Component - Formula: H2O / Component - Name: Distilled water
GridModel: C-flat-1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK III / Details: blot for 9s before plunging.
DetailsSample in pure water, pH not determined

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specialist opticsEnergy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 1 / Number real images: 3032 / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Segment selectionNumber selected: 43308
Details: manual particle picking helical start-end coordinates
CTF correctionSoftware - Name: Gctf (ver. 1.06)
Details: CTF was estimated from the non-dose-weighted micrographs
Startup modelType of model: NONE
Details: Initial model generation in RELION, followed by a 3D classification of particles picked from 28 micrographs to generate rough 3D model which was used as a reference
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.76311 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.45566 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 43308
DetailsMotion-corrected and dose-weighted movie frames
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsSecondary structure restraints and NCS were applied during refinement
RefinementSpace: REAL / Protocol: OTHER
Target criteria: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Output model

PDB-7nsl:
AL amyloid fibril from a lambda 1 light chain

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