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- EMDB-46496: Cryo-EM structure of amyloid fibril extracted from heart of a var... -

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Entry
Database: EMDB / ID: EMD-46496
TitleCryo-EM structure of amyloid fibril extracted from heart of a variant ATTR T60A amyloidosis patient 3
Map datapost-processed map
Sample
  • Tissue: Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient
    • Protein or peptide: Transthyretin
KeywordsTransthyretin / Amyloidosis / ATTR / Heart / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 4.64 Å
AuthorsNguyen AB / Fernandez-Ramirez MC / 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: Structure / Year: 2025
Title: Structural and molecular homogeneity of ATTRv-T60A amyloid fibrils across patients and organs.
Authors: Maria Del Carmen Fernandez-Ramirez / Binh A Nguyen / Shumaila Afrin / Virender Singh / Bret Evers / John M Shelton / Christian Lopez Escobar / Parker Bassett / Lanie Wang / Maja Pękała / ...Authors: Maria Del Carmen Fernandez-Ramirez / Binh A Nguyen / Shumaila Afrin / Virender Singh / Bret Evers / John M Shelton / Christian Lopez Escobar / Parker Bassett / Lanie Wang / Maja Pękała / Yasmin Ahmed / Luis O Cabrera Hernandez / Rose Pedretti / Preeti Singh / Jacob Canepa / Aleksandra Wosztyl / Yang Li / David R Boyer / Qin Cao / Lorena Saelices /
Abstract: Transthyretin amyloidosis is a systemic protein misfolding disorder with diverse clinical phenotypes, including cardiomyopathy, polyneuropathy, or a combination of both. While structural polymorphism ...Transthyretin amyloidosis is a systemic protein misfolding disorder with diverse clinical phenotypes, including cardiomyopathy, polyneuropathy, or a combination of both. While structural polymorphism of amyloid fibrils has been linked to disease heterogeneity in neurodegenerative disorders, its role in transthyretin amyloidosis remains unclear. Here, we used cryo-electron microscopy to analyze ex vivo fibrils extracted from the hearts of three patients carrying the T60A mutation, a variant associated with mixed cardiac and neuropathic symptoms. In one patient, we additionally examined fibrils from the thyroid, kidney, and liver. All fibrils across patients and tissues adopted a single morphology previously associated with cardiomyopathy. Complementary molecular analyses revealed high compositional homogeneity. Notably, we extracted fibrils from the liver, an organ considered fibril-free, with seeding capacity in vitro. These findings suggest structural homogeneity as a hallmark of cardiac and mixed phenotypes, and provide a mechanistic rationale for the transmission of amyloidosis following domino liver transplantation.
History
DepositionAug 8, 2024-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateDec 17, 2025-
Current statusDec 17, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46496.png

Downloads & links

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Map

FileDownload / File: emd_46496.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpost-processed map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 213.504 Å		0.83 Å/pix.
x 256 pix.
= 213.504 Å		0.83 Å/pix.
x 256 pix.
= 213.504 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0038
Minimum - Maximum-0.014068701 - 0.01924958
Average (Standard dev.)0.00006118065 (±0.0006923243)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 213.504 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46496_msk_1.map
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Additional map: combined map from two half-maps

Fileemd_46496_additional_1.map
Annotationcombined map from two half-maps
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Half map: half-map 01

Fileemd_46496_half_map_1.map
Annotationhalf-map 01
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Half map: half-map 02

Fileemd_46496_half_map_2.map
Annotationhalf-map 02
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Sample components

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Entire : Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient

EntireName: Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient
Components
  • Tissue: Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient
    • Protein or peptide: Transthyretin

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Supramolecule #1: Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient

SupramoleculeName: Amyloid fibril from heart of a variant ATTR T60A amyloidosis patient
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart

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Macromolecule #1: Transthyretin

MacromoleculeName: Transthyretin / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart
SequenceString:
GPTGTGESKC PLMVKVLDAV RGSPAINVAV HVFRKAADDT WEPFASGKTS ESGELHGLTA EEEFVEGIYK VEIDTKSYWK ALGISPFHEH AEVVFTANDS GPRRYTIAAL LSPYSYSTTA VVTNPKE

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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: We used water as the buffer for the final elution of fibrils
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 6064 / Average exposure time: 1.8 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: 2.2 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: 2
Applied symmetry - Helical parameters - Δz: 4.79 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.25 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.64 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 49669
CTF correctionSoftware - Name: RELION (ver. 4.0) / Software - details: CTFFIND-4.1 / Type: NONE
Segment selectionNumber selected: 207988 / Software - Name: Topaz / Details: particle boxsize of 256 px
Startup modelType of model: OTHER / Details: Featureless cylinder
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsWe did not build the model for this map

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