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- EMDB-46479: Cryo-EM structure of amyloid fibril extracted from heart of a var... -

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Basic information

Entry
Database: EMDB / ID: EMD-46479
TitleCryo-EM structure of amyloid fibril extracted from heart of a variant ATTR T60A amyloidosis patient 1
Map datawas used for model-building
Sample
  • Tissue: Cardiac amyloid fibril of a variant ATTR T60A amyloidosis patient
    • Protein or peptide: Transthyretin
KeywordsTransthyretin / 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) / hormone binding / purine nucleobase metabolic process / molecular sequestering activity / Non-integrin membrane-ECM interactions / phototransduction, visible light / retinoid metabolic process / Retinoid metabolism and transport ...Defective visual phototransduction due to STRA6 loss of function / negative regulation of glomerular filtration / The canonical retinoid cycle in rods (twilight vision) / hormone binding / purine nucleobase metabolic process / molecular sequestering activity / Non-integrin membrane-ECM interactions / phototransduction, visible light / retinoid metabolic process / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation / protein-containing complex binding / protein-containing complex / 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: 3.4 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-
UpdateOct 29, 2025-
Current statusOct 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46479.png

Downloads & links

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Map

FileDownload / File: emd_46479.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationwas used for model-building
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 320 pix.
= 337.6 Å		1.06 Å/pix.
x 320 pix.
= 337.6 Å		1.06 Å/pix.
x 320 pix.
= 337.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.055 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 14.300000000000001
Minimum - Maximum-29.789068 - 51.220256999999997
Average (Standard dev.)0.000000000004952 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 337.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46479_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: combined map from 2 half-maps

Fileemd_46479_additional_1.map
Annotationcombined map from 2 half-maps
Projections & Slices
AxesZYX

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Histogram

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Half map: half-map 01

Fileemd_46479_half_map_1.map
Annotationhalf-map 01
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half-map 02

Fileemd_46479_half_map_2.map
Annotationhalf-map 02
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Cardiac amyloid fibril of a variant ATTR T60A amyloidosis patient

EntireName: Cardiac amyloid fibril of a variant ATTR T60A amyloidosis patient
Components
  • Tissue: Cardiac amyloid fibril of a variant ATTR T60A amyloidosis patient
    • Protein or peptide: Transthyretin

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Supramolecule #1: Cardiac amyloid fibril of a variant ATTR T60A amyloidosis patient

SupramoleculeName: Cardiac amyloid fibril 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: Cardiac

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Macromolecule #1: Transthyretin

MacromoleculeName: Transthyretin / type: protein_or_peptide / ID: 1 / Details: amyloid fibril / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Heart / Tissue: Cardiac
Molecular weightTheoretical: 13.747334 KDa
SequenceString:
GPTGTGESKC PLMVKVLDAV RGSPAINVAV HVFRKAADDT WEPFASGKTS ESGELHGLTA EEEFVEGIYK VEIDTKSYWK ALGISPFHE 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
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: 3735 / Average electron dose: 42.0 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: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.27 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 55692
CTF correctionSoftware - Name: RELION (ver. 3.1) / Software - details: CTFFIND-4.1 / Type: NONE
Segment selectionNumber selected: 226710 / Software - Name: EMAN2 (ver. 2.31) / Details: particle boxsize of 256 px
Startup modelType of model: OTHER / Details: Featureless cylinder
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 3.1)

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Atomic model buiding 1

Initial modelPDB ID:

6sdz


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9d21:
Cryo-EM structure of amyloid fibril extracted from heart of a variant ATTR T60A amyloidosis patient 1

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