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- PDB-9zld: Cryo-EM structure of hepatic amyloid fibril from a variant ATTRV1... -

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Basic information

Entry
Database: PDB / ID: 9zld
TitleCryo-EM structure of hepatic amyloid fibril from a variant ATTRV122delta, single filament morphology
ComponentsTransthyretin
KeywordsPROTEIN FIBRIL / ATTR / Systemic amyloidosis / V122delta / amyloid
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: 2.9 Å
AuthorsNguyen, B.A. / Ahmed, Y. / Saelices, L.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)DP2-HL163810 United States
American Heart Association847236 United States
Welch FoundationI-2121-20220331 United States
Citation
Journal: Nat Commun / Year: 2026
Title: Cryo-EM reveals structural variability of apolipoprotein A-I amyloid fibrils across organs, mutations, and clinical presentations.
Authors: Binh An Nguyen / Maria Del Carmen Fernandez-Ramirez / Parker Bassett / Virender Singh / Preeti Singh / Maja Pękała / Layla Villalon / Yasmin Ahmed / Andrew Lemoff / Bret Evers / Christian ...Authors: Binh An Nguyen / Maria Del Carmen Fernandez-Ramirez / Parker Bassett / Virender Singh / Preeti Singh / Maja Pękała / Layla Villalon / Yasmin Ahmed / Andrew Lemoff / Bret Evers / Christian Lopez / Barbara Kluve-Beckerman / Lorena Saelices /
Abstract: Hereditary apolipoprotein A-I (AApoA‑I) amyloidosis is a rare systemic disease caused by the deposition of amyloid fibrils formed by apolipoprotein A‑I in multiple organs, leading to severe ...Hereditary apolipoprotein A-I (AApoA‑I) amyloidosis is a rare systemic disease caused by the deposition of amyloid fibrils formed by apolipoprotein A‑I in multiple organs, leading to severe clinical outcomes. With no available therapies or diagnostic tools, defining the structure of AApoA‑I fibrils is crucial to understanding disease mechanisms and guiding intervention. Here we use cryo-electron microscopy to analyze AApoA‑I fibrils from the heart, kidney, liver, and spleen of patients carrying G26R, L90P, and R173P mutations. G26R fibrils, regardless of organ, exhibits untwisted morphologies and cannot be resolved structurally. Conversely, L90P and R173P fibrils display a compact diabolo-shaped conformation in all organs analyzed. Their high-resolution maps enable visualization of cis-Proline 66, which may represent a potential conformational switch during fibril formation. Our findings suggest that mutation-driven polymorphism may influence organ tropism and clinical presentation. This work advances our understanding of AApoA‑I fibril assembly and provides insights toward developing targeted clinical tools.
#1: Journal: Commun Biol / Year: 2026
Title: Amyloid fibril polymorphism in the heart and liver of a patient with polyneuropathic ATTRv-V122Δ amyloidosis.
Authors: Yasmin Ahmed / Binh An Nguyen / Candace Kelly / Shumaila Afrin / Virender Singh / Bret M Evers / John M Shelton / Christian Lopez Escobar / Preeti Singh / Rose Pedretti / Lanie Wang / Parker ...Authors: Yasmin Ahmed / Binh An Nguyen / Candace Kelly / Shumaila Afrin / Virender Singh / Bret M Evers / John M Shelton / Christian Lopez Escobar / Preeti Singh / Rose Pedretti / Lanie Wang / Parker Bassett / Maria Del Carmen Fernandez-Ramirez / Maja Pekala / Andrew Lemoff / Barbara Kluve-Beckerman / Lorena Saelices /
Abstract: ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may ...ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may result from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from multisystem organ involvement. Over 220 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in explaining differential disease manifestations remains unclear. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart and the liver of an ATTRv patient carrying the V122∆ mutation, which is predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.
History
DepositionDec 8, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 15, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.1Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / Item: _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


Theoretical massNumber of molelcules
Total (without water)68,3915
Polymers68,3915
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: 13678.229 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Liver / Tissue: Liver / 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: fibrils of ATTRV122delta / Type: COMPLEX / Details: fibril extracted from the liver, postmortem. / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Organ: Liver / Tissue: Liver
Buffer solutionpH: 7 / Details: ice-chilled water
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: fibrils were extracted from cardiac tissue using a water-based extraction method.
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: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingAverage exposure time: 2.06 sec. / Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4366

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2SerialEM4.1.5image acquisition
4CTFFIND4.1CTF correction
7Coot0.9.8.1model fitting
9PHENIX1.20.1model refinement
10RELION4initial Euler assignment
11RELION4final Euler assignment
12RELION4classification
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
Helical symmertyAngular rotation/subunit: -1.19 ° / Axial rise/subunit: 4.82 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 345559
Details: Initial segment after extraction at box size of 300 pixel
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21384 / Symmetry type: HELICAL
Atomic model buildingB value: 49.97 / Protocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 8BDM

8bdm


Pdb chain-ID: A / Accession code: 8BDM / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033660
ELECTRON MICROSCOPYf_angle_d0.5794980
ELECTRON MICROSCOPYf_dihedral_angle_d5.316490
ELECTRON MICROSCOPYf_chiral_restr0.05585
ELECTRON MICROSCOPYf_plane_restr0.005615

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