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- PDB-9pvy: Cryo-EM structure of cardiac amyloid fibril from a variant apolip... -

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Basic information

Entry
Database: PDB / ID: 9pvy
TitleCryo-EM structure of cardiac amyloid fibril from a variant apolipoprotein A-I L90P amyloidosis patient
ComponentsApolipoprotein A-I
KeywordsPROTEIN FIBRIL / Apolipoprotein A-I / AApoAI / L90P / Amyloidosis.
Function / homology
Function and homology information


Defective ABCA1 causes TGD / high-density lipoprotein particle receptor binding / peptidyl-methionine modification / HDL clearance / spherical high-density lipoprotein particle / Scavenging by Class B Receptors / negative regulation of response to cytokine stimulus / protein oxidation / regulation of intestinal cholesterol absorption / vitamin transport ...Defective ABCA1 causes TGD / high-density lipoprotein particle receptor binding / peptidyl-methionine modification / HDL clearance / spherical high-density lipoprotein particle / Scavenging by Class B Receptors / negative regulation of response to cytokine stimulus / protein oxidation / regulation of intestinal cholesterol absorption / vitamin transport / blood vessel endothelial cell migration / cholesterol import / negative regulation of heterotypic cell-cell adhesion / apolipoprotein A-I receptor binding / ABC transporters in lipid homeostasis / apolipoprotein receptor binding / negative regulation of cell adhesion molecule production / HDL assembly / negative regulation of cytokine production involved in immune response / high-density lipoprotein particle binding / negative regulation of very-low-density lipoprotein particle remodeling / glucocorticoid metabolic process / acylglycerol homeostasis / phosphatidylcholine biosynthetic process / phosphatidylcholine-sterol O-acyltransferase activator activity / positive regulation of phospholipid efflux / Chylomicron remodeling / cellular response to lipoprotein particle stimulus / Chylomicron assembly / high-density lipoprotein particle clearance / phospholipid efflux / chylomicron / high-density lipoprotein particle remodeling / reverse cholesterol transport / positive regulation of cholesterol metabolic process / lipid storage / high-density lipoprotein particle assembly / phospholipid homeostasis / chemorepellent activity / lipoprotein biosynthetic process / cholesterol transfer activity / cholesterol transport / low-density lipoprotein particle / high-density lipoprotein particle / very-low-density lipoprotein particle / endothelial cell proliferation / regulation of Cdc42 protein signal transduction / HDL remodeling / cholesterol efflux / adrenal gland development / Scavenging by Class A Receptors / triglyceride homeostasis / negative regulation of interleukin-1 beta production / negative chemotaxis / cholesterol binding / cholesterol biosynthetic process / amyloid-beta formation / positive regulation of Rho protein signal transduction / positive regulation of cholesterol efflux / endocytic vesicle / negative regulation of tumor necrosis factor-mediated signaling pathway / Scavenging of heme from plasma / cholesterol metabolic process / Retinoid metabolism and transport / positive regulation of stress fiber assembly / heat shock protein binding / endocytic vesicle lumen / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / cholesterol homeostasis / integrin-mediated signaling pathway / Post-translational protein phosphorylation / Heme signaling / PPARA activates gene expression / phospholipid binding / negative regulation of inflammatory response / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Platelet degranulation / amyloid-beta binding / extracellular vesicle / cytoplasmic vesicle / secretory granule lumen / blood microparticle / early endosome / protein stabilization / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / Amyloid fiber formation / receptor ligand activity / signaling receptor binding / enzyme binding / protein homodimerization activity / : / extracellular exosome / extracellular region / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Apolipoprotein A/E / : / Apolipoprotein A1/A4/E domain
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.15 Å
AuthorsNguyen, B.A. / Saelices, L.
Funding support United States, 3items
OrganizationGrant numberCountry
American Heart Association847236 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)DP2-HL163810 United States
Welch FoundationI-2121-20220331 United States
CitationJournal: 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.
History
DepositionAug 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 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
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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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Apolipoprotein A-I
B: Apolipoprotein A-I
C: Apolipoprotein A-I
D: Apolipoprotein A-I
E: Apolipoprotein A-I
F: Apolipoprotein A-I
G: Apolipoprotein A-I
H: Apolipoprotein A-I
I: Apolipoprotein A-I
J: Apolipoprotein A-I


Theoretical massNumber of molelcules
Total (without water)281,20610
Polymers281,20610
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
Apolipoprotein A-I / Apolipoprotein A-I(1-242)


Mass: 28120.637 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: HEART / Tissue: heart / References: UniProt: P02647
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: amyloid fibrils of apoliprotein A-I amyloidosis, variant L90P
Type: COMPLEX
Details: fibrils were extracted from cardiac tissue of a variant apolipoprotein A-I L90P amyloidosis
Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human) / Organ: heart / Tissue: heart
Buffer solutionpH: 7 / Details: H2O containing 5 mM EDTA
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: 2600 nm / Nominal defocus min: 800 nm
Image recordingAverage exposure time: 5 sec. / Electron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 12645

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2EPUimage acquisition
4CTFFINDCTF correction
9RELION4initial Euler assignment
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionDetails: RELION 4 built in CTFFIND / Type: NONE
Helical symmertyAngular rotation/subunit: -0.68 ° / Axial rise/subunit: 4.85 Å / Axial symmetry: C1
3D reconstructionResolution: 2.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118342 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: OTHER / Space: REAL
Details: This is a novel structure. Model was built using the protein primary sequence by COOT
RefinementHighest resolution: 2.15 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032450
ELECTRON MICROSCOPYf_angle_d0.7373320
ELECTRON MICROSCOPYf_dihedral_angle_d5.513315
ELECTRON MICROSCOPYf_chiral_restr0.042375
ELECTRON MICROSCOPYf_plane_restr0.003420

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