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- PDB-6hud: Cryo-EM structure of cardiac amyloid fibrils from an immunoglobul... -

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Entry
Database: PDB / ID: 6hud
TitleCryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain (AL) amyloidosis patient.
ComponentsMonoclonal immunoglobulin light chains (LC)
KeywordsPROTEIN FIBRIL / immunoglobulin light chains / amyloid cardiomyopathy / ex-vivo cryo-EM / helical reconstruction
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4 Å
AuthorsPaissoni, C. / Camilloni, C.
Funding support Italy, 4items
OrganizationGrant numberCountry
Italian Association for Cancer Research9965 Italy
Fondazione CARIPLO
Italian Ministry of Health
Italian Medicines Agency
CitationJournal: Nat Commun / Year: 2019
Title: Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient.
Authors: Paolo Swuec / Francesca Lavatelli / Masayoshi Tasaki / Cristina Paissoni / Paola Rognoni / Martina Maritan / Francesca Brambilla / Paolo Milani / Pierluigi Mauri / Carlo Camilloni / Giovanni ...Authors: Paolo Swuec / Francesca Lavatelli / Masayoshi Tasaki / Cristina Paissoni / Paola Rognoni / Martina Maritan / Francesca Brambilla / Paolo Milani / Pierluigi Mauri / Carlo Camilloni / Giovanni Palladini / Giampaolo Merlini / Stefano Ricagno / Martino Bolognesi /
Abstract: Systemic light chain amyloidosis (AL)  is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart ...Systemic light chain amyloidosis (AL)  is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V) fit the fibril density. Despite V high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.
History
DepositionOct 6, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
A: Monoclonal immunoglobulin light chains (LC)
B: Monoclonal immunoglobulin light chains (LC)
C: Monoclonal immunoglobulin light chains (LC)
D: Monoclonal immunoglobulin light chains (LC)
E: Monoclonal immunoglobulin light chains (LC)


Theoretical massNumber of molelcules
Total (without water)73,1045
Polymers73,1045
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy, native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27250 Å2
ΔGint-90 kcal/mol
Surface area17560 Å2
MethodPISA

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Components

#1: Antibody
Monoclonal immunoglobulin light chains (LC)


Mass: 14620.864 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Heart

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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: Cardiac amyloid fibril from an immunoglobulin light chain (AL) amyloidosis patient
Type: COMPLEX / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Tissue: Heart
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal magnification: 120000 X / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER
Image recordingAverage exposure time: 1 sec. / Electron dose: 50 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 1680

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameVersionCategory
1RELION2.1beta1particle selection
2EPU1.9image acquisition
4CTFFIND4.1.10CTF correction
9RELION2.1beta1initial Euler assignment
10RELIONv2.1beta1final Euler assignment
11RELION2.1beta1classification
12RELION2.1beta13D reconstruction
13PHENIX1.13model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.608 ° / Axial rise/subunit: 4.903 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 104689
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21031 / Symmetry type: HELICAL
Atomic model buildingSpace: REAL

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