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- EMDB-29874: Cardiac amyloid fibrils extracted from a wild-type ATTR amyloidos... -

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Entry
Database: EMDB / ID: EMD-29874
TitleCardiac amyloid fibrils extracted from a wild-type ATTR amyloidosis patient
Map dataCardiac amyloid fibrils extracted from a wild-type ATTR amyloidosis patient
Sample
  • Tissue: cardiac amyloid fibril of wild-type transthyretin amyloidosis
    • Protein or peptide: Transthyretin
KeywordsTransthyretin / Amyloidosis / Systemic amyloidosis / ATTR / Cardiac / PROTEIN FIBRIL
Function / homology
Function and homology information


Defective visual phototransduction due to STRA6 loss of function / negative regulation of glomerular filtration / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / molecular sequestering activity / phototransduction, visible light / Non-integrin membrane-ECM interactions / retinoid metabolic process / Retinoid metabolism and transport / hormone activity ...Defective visual phototransduction due to STRA6 loss of function / negative regulation of glomerular filtration / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / molecular sequestering activity / phototransduction, visible light / Non-integrin membrane-ECM interactions / retinoid metabolic process / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation / extracellular space / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
Transthyretin, conserved site / Transthyretin signature 2. / Transthyretin, thyroxine binding site / Transthyretin signature 1. / Transthyretin / Transthyretin/hydroxyisourate hydrolase / Transthyretin/hydroxyisourate hydrolase domain / Transthyretin/hydroxyisourate hydrolase domain superfamily / HIUase/Transthyretin family
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsNguyen BA / Saelices L
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)1DP2HL163810-01 United States
American Heart Association847236 United States
CitationJournal: Commun Biol / Year: 2024
Title: Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.
Authors: Binh An Nguyen / Virender Singh / Shumaila Afrin / Preeti Singh / Maja Pekala / Yasmin Ahmed / Rose Pedretti / Jacob Canepa / Andrew Lemoff / Barbara Kluve-Beckerman / Pawel M Wydorski / ...Authors: Binh An Nguyen / Virender Singh / Shumaila Afrin / Preeti Singh / Maja Pekala / Yasmin Ahmed / Rose Pedretti / Jacob Canepa / Andrew Lemoff / Barbara Kluve-Beckerman / Pawel M Wydorski / Farzeen Chhapra / Lorena Saelices /
Abstract: ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv ...ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.
History
DepositionFeb 21, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29874.png

Downloads & links

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Map

FileDownload / File: emd_29874.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCardiac amyloid fibrils extracted from a wild-type ATTR amyloidosis patient
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.023430273 - 0.048177116
Average (Standard dev.)0.0001293903 (±0.002615679)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29874_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: this map is calibrated and sharpened to build the model.

Fileemd_29874_additional_1.map
Annotationthis map is calibrated and sharpened to build the model.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 1

Fileemd_29874_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_29874_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : cardiac amyloid fibril of wild-type transthyretin amyloidosis

EntireName: cardiac amyloid fibril of wild-type transthyretin amyloidosis
Components
  • Tissue: cardiac amyloid fibril of wild-type transthyretin amyloidosis
    • Protein or peptide: Transthyretin

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Supramolecule #1: cardiac amyloid fibril of wild-type transthyretin amyloidosis

SupramoleculeName: cardiac amyloid fibril of wild-type transthyretin amyloidosis
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Cardiac

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Macromolecule #1: Transthyretin

MacromoleculeName: Transthyretin / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart
Molecular weightTheoretical: 15.904984 KDa
SequenceString:
MASHRLLLLC LAGLVFVSEA GPTGTGESKC PLMVKVLDAV RGSPAINVAV HVFRKAADDT WEPFASGKTS ESGELHGLTT EEEFVEGIY KVEIDTKSYW KALGISPFHE HAEVVFTAND SGPRRYTIAA LLSPYSYSTT AVVTNPKE

UniProtKB: Transthyretin

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 7 / Details: H2O, 5 mM EDTA
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV
Detailscardiac fibrils were extracted using water-extraction protocol.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.81 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.96 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.35 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 37947
Startup modelType of model: OTHER / Details: Featureless cylinder
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8e7d


Chain - Source name: Other / Chain - Initial model type: other
RefinementProtocol: OTHER
Output model

PDB-8g9r:
Cardiac amyloid fibrils extracted from a wild-type ATTR amyloidosis patient

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