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- EMDB-50270: Cryo-EM structure of cardiac collagen-associated amyloid AL59 -

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Basic information

Entry
Database: EMDB / ID: EMD-50270
TitleCryo-EM structure of cardiac collagen-associated amyloid AL59
Map data
Sample
  • Tissue: Monoclonal immunoglobulin light chains (LC), fibrillar form
    • Protein or peptide: Monoclonal immunoglobulin light chains (LC)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordssystemic AL amyloid fibril / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsSchulte T / Speranzini V / Chaves-Sanjuan A / Milazzo M / Ricagno S
Funding support Italy, 1 items
OrganizationGrant numberCountry
Italian Ministry of EducationPRIN 2020 (20207XLJB2) Italy
CitationJournal: Nat Commun / Year: 2024
Title: Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis.
Authors: Tim Schulte / Antonio Chaves-Sanjuan / Valentina Speranzini / Kevin Sicking / Melissa Milazzo / Giulia Mazzini / Paola Rognoni / Serena Caminito / Paolo Milani / Chiara Marabelli / ...Authors: Tim Schulte / Antonio Chaves-Sanjuan / Valentina Speranzini / Kevin Sicking / Melissa Milazzo / Giulia Mazzini / Paola Rognoni / Serena Caminito / Paolo Milani / Chiara Marabelli / Alessandro Corbelli / Luisa Diomede / Fabio Fiordaliso / Luigi Anastasia / Carlo Pappone / Giampaolo Merlini / Martino Bolognesi / Mario Nuvolone / Rubén Fernández-Busnadiego / Giovanni Palladini / Stefano Ricagno /
Abstract: Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC ...Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.
History
DepositionMay 10, 2024-
Header (metadata) releaseJul 17, 2024-
Map releaseJul 17, 2024-
UpdateAug 14, 2024-
Current statusAug 14, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50270.png

Downloads & links

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Map

FileDownload / File: emd_50270.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.889 Å
Density
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.050183404 - 0.089822
Average (Standard dev.)0.00023353202 (±0.0025303403)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 302.26 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50270_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_50270_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_50270_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Monoclonal immunoglobulin light chains (LC), fibrillar form

EntireName: Monoclonal immunoglobulin light chains (LC), fibrillar form
Components
  • Tissue: Monoclonal immunoglobulin light chains (LC), fibrillar form
    • Protein or peptide: Monoclonal immunoglobulin light chains (LC)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Monoclonal immunoglobulin light chains (LC), fibrillar form

SupramoleculeName: Monoclonal immunoglobulin light chains (LC), fibrillar form
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Amyloid fibrils extracted ex vivo from cardiac tissue of AL patient
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Monoclonal immunoglobulin light chains (LC)

MacromoleculeName: Monoclonal immunoglobulin light chains (LC) / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.923335 KDa
SequenceString:
SFELTQPSSV SVSPGQTANI TCSGGYLGET YRSWYQQKPG QSPVLVIYQS SKRPSGIPGR FSGSNSGNTA TLTISGTQPL DEADYFCQA WDFTSVVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATL

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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 / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number real images: 2049 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 120000
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.9158 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.7425 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 37904
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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