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- PDB-9px6: ATTR cardiac amyloid fibrils apex1 -

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Basic information

Entry
Database: PDB / ID: 9px6
TitleATTR cardiac amyloid fibrils apex1
ComponentsTransthyretin
KeywordsPROTEIN FIBRIL / Transthyretin / amyloidosis
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 / hormone binding / Non-integrin membrane-ECM interactions / phototransduction, visible light / molecular sequestering activity / 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) / purine nucleobase metabolic process / hormone binding / Non-integrin membrane-ECM interactions / phototransduction, visible light / molecular sequestering activity / 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 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSchaefer, J.H. / Lander, G.C.
Funding support United States, Germany, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS095892 United States
German Research Foundation (DFG)556478029 Germany
CitationJournal: J Am Heart Assoc / Year: 2026
Title: Three-Dimensional Visualization and Proteomic Analysis of Human Cardiac Transthyretin Amyloidosis Tissue Reveals Microangiopathy and Capillary Occlusion.
Authors: Joseph P Donnelly / Jan-Hannes Schäfer / Leonard Yoon / Lynée A Massey / Carl Ash / Zi Gao / Karina Nugroho / Marcus Jäger / Zhengyuan Pang / Robert T O'Neill / Mathew S Maurer / Evan T ...Authors: Joseph P Donnelly / Jan-Hannes Schäfer / Leonard Yoon / Lynée A Massey / Carl Ash / Zi Gao / Karina Nugroho / Marcus Jäger / Zhengyuan Pang / Robert T O'Neill / Mathew S Maurer / Evan T Powers / Gabriel C Lander / Li Ye / Jeffery W Kelly /
Abstract: BACKGROUND: Transthyretin amyloidosis (ATTR) is a degenerative disease affecting the heart and other organs. Transthyretin (TTR) aggregation is a driver of ATTR pathology, but the mechanism is poorly ...BACKGROUND: Transthyretin amyloidosis (ATTR) is a degenerative disease affecting the heart and other organs. Transthyretin (TTR) aggregation is a driver of ATTR pathology, but the mechanism is poorly understood. We used proteomics and tissue clearing technology on wild-type (WT) human cardiac (WT/WT) and V122I human cardiac (V122I/WT) tissue to better understand TTR cardiomyopathy.
METHODS: Flash-frozen cardiac tissue slices from human subjects with end-stage WT-TTR cardiomyopathy, end-stage V122I TTR cardiomyopathy, and an age-matched control were used. Fibrils and tissue ...METHODS: Flash-frozen cardiac tissue slices from human subjects with end-stage WT-TTR cardiomyopathy, end-stage V122I TTR cardiomyopathy, and an age-matched control were used. Fibrils and tissue proteomes were extracted and assessed by bottom-up proteomics. Tissue clearing was performed using a lauryl sulfate-based lipid removal strategy. Slices were stained using indirect immunofluorescence against targets identified by proteomics. TTR deposits were imaged by antibody and AmyTracker 480 staining. Structures of ATTR fibrils were characterized using cryogenic electron microscopy.
RESULTS: Proteomic analysis revealed high abundance of TTR, proteins associated with amyloid fibrils, as well as angiogenic, hemostatic, and complement cascade-associated proteins. Three-dimensional ...RESULTS: Proteomic analysis revealed high abundance of TTR, proteins associated with amyloid fibrils, as well as angiogenic, hemostatic, and complement cascade-associated proteins. Three-dimensional imaging revealed loss of normal microvascular architecture, regions of hypervascularization and hypovascularization, and microvascular obstruction by capillary thrombosis. ATTR fibrils adopted the spearhead fold and were decorated with collagen VI, an extracellular matrix component.
CONCLUSIONS: Based on our imaging and proteomic data, we hypothesize that ATTR cardiomyopathy is a microangiopathy driven by capillary bed thromboinflammation and dysregulated angiogenic ...CONCLUSIONS: Based on our imaging and proteomic data, we hypothesize that ATTR cardiomyopathy is a microangiopathy driven by capillary bed thromboinflammation and dysregulated angiogenic revascularization. In this model, increased capillary permeability exposes components of the vascular basement membrane to misfolded TTR. These components promote aggregation and stabilize amyloid fibrils. Congestion of the vascular basement membrane prevents appropriate revascularization, reducing cardiac exertional capacity over time, leading to heart failure.
History
DepositionAug 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2026Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2026Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update
Revision 1.1Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / Item: _citation.journal_volume / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transthyretin
B: Transthyretin
C: Transthyretin
D: Transthyretin
E: Transthyretin
F: Transthyretin


Theoretical massNumber of molelcules
Total (without water)95,4306
Polymers95,4306
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transthyretin / ATTR / Prealbumin / TBPA


Mass: 15904.984 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P02766
Has protein modificationN

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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: Transthyretin amyloid fibril / Type: COMPLEX / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.26 ° / Axial rise/subunit: 4.85 Å / Axial symmetry: C1
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 171067 / Symmetry type: HELICAL
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034386
ELECTRON MICROSCOPYf_angle_d0.6045970
ELECTRON MICROSCOPYf_dihedral_angle_d6.395588
ELECTRON MICROSCOPYf_chiral_restr0.051708
ELECTRON MICROSCOPYf_plane_restr0.005732

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