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

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Basic information

Entry
Database: PDB / ID: 7nsl
TitleAL amyloid fibril from a lambda 1 light chain
ComponentsAmyloid lambda1 light chain
KeywordsIMMUNE SYSTEM / amyloid / antibody / systemic amyloidosis / light chain
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsKarimi Farsijani, S. / Radamaker, L. / Fandrich, M.
Funding support Germany, 1items
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, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
D: Amyloid lambda1 light chain
E: Amyloid lambda1 light chain
F: Amyloid lambda1 light chain
C: Amyloid lambda1 light chain
B: Amyloid lambda1 light chain
A: Amyloid lambda1 light chain
G: Amyloid lambda1 light chain


Theoretical massNumber of molelcules
Total (without water)84,8567
Polymers84,8567
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry, Guanidinium hydrochloride?
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody
Amyloid lambda1 light chain


Mass: 12122.354 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Heart / Plasmid details: AL amyloidosis patient / Tissue: Heart muscle tissue

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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 of an antibody lambda 1 immunoglobulin light chain
Type: COMPLEX
Details: Extracted fibrils from the explanted heart of a patient suffering from systemic AL amyloidosis
Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart muscle
Buffer solutionpH: 7
Buffer componentName: Distilled water / Formula: H2O
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Sample in pure water, pH not determined
Specimen supportGrid material: COPPER / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295 K / Details: blot for 9s before plunging

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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 / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3032
EM imaging opticsEnergyfilter slit width: 20 eV
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 40

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Processing

EM software
IDNameVersionCategoryDetails
2SerialEMimage acquisition
4Gctf1.06CTF correction
7Coot0.8.9.2model fittingBackbone was traced using baton mode; backbone mutated to the protein sequence; real-space refinement with restraints
12RELION33D reconstruction
13PHENIX1.16model refinementphenix.real_space_refine
Image processingDetails: Motion-corrected and dose-weighted movie frames
CTF correctionDetails: CTF was estimated from the non-dose-weighted micrographs
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.45566 ° / Axial rise/subunit: 4.76311 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 43308
Details: manual particle picking helical start-end coordinates
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 43308 / Symmetry type: HELICAL
Atomic model buildingProtocol: OTHER / Space: REAL
Target criteria: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Details: Secondary structure restraints and NCS were applied during refinement

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