EMDB-71897: Cryo-EM structure of cardiac amyloid fibril from a variant apolip...

Basic information

Entry

Database: EMDB / ID: EMD-71897

• Title: Cryo-EM structure of cardiac amyloid fibril from a variant apolipoprotein A-I R173P amyloidosis patient
• Map data: primary map for building model

Sample

• Complex: amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P from cardiac tissue
  • Protein or peptide: Apolipoprotein A-I

• Keywords: Apolipoprotein A-I / AApoAI / R173P / cardiac / amyloidosis. / PROTEIN FIBRIL

Function / homology

Function:

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

Domain/homology:

Apolipoprotein A/E / : / Apolipoprotein A1/A4/E domain

Component:

Apolipoprotein A-I

• Biological species: Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 2.3 Å
• Authors: Nguyen BA / Saelices L

Funding support

United States, 3 items

Organization	Grant number	Country
American Heart Association	847236	United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)	DP2-HL163810	United States
Welch Foundation	I-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 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 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

Deposition	Aug 4, 2025	-
Header (metadata) release	Mar 18, 2026	-
Map release	Mar 18, 2026	-
Update	Apr 29, 2026	-
Current status	Apr 29, 2026	Processing site: RCSB / Status: Released

Map

• File: Download / File: emd_71897.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Annotation: primary map for building model
• Voxel size: X=Y=Z: 0.932 Å

Density

Contour Level	By AUTHOR: 0.0282
Minimum - Maximum	-0.108131826 - 0.2383573
Average (Standard dev.)	0.0001389667 (±0.0045794337)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 300 300 300 Spacing 300 300 300
Cell	A=B=C: 279.6 Å α=β=γ: 90.0 °

Supplemental data

Mask #1

• File: emd_71897_msk_1.map

Additional map: combined map from two half-maps

• File: emd_71897_additional_1.map
• Annotation: combined map from two half-maps

Half map: half-map 01

• File: emd_71897_half_map_1.map
• Annotation: half-map 01

Half map: half-map 02

• File: emd_71897_half_map_2.map
• Annotation: half-map 02

Sample components

Entire : amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P fr...

• Entire: Name: amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P from cardiac tissue

Components

• Complex: amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P from cardiac tissue
  • Protein or peptide: Apolipoprotein A-I

Supramolecule #1: amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P fr...

• Supramolecule: Name: amyloid fibrils of apoliprotein A-I amyloidosis, variant R173P from cardiac tissue; type: complex / ID: 1 / Parent: 0 / Macromolecule list: all; Details: fibrils were extracted from cardiac tissue of a variant apolipoprotein A-I R173P amyloidosis
• Source (natural): Organism: Homo sapiens (human) / Organ: heart / Tissue: heart

Macromolecule #1: Apolipoprotein A-I

• Macromolecule: Name: Apolipoprotein A-I / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
• Source (natural): Organism: Homo sapiens (human) / Organ: Heart / Tissue: Heart
• Molecular weight: Theoretical: 28.120637 KDa

Sequence

String:

DEPPQSPWDR VKDLATVYVD VLKDSGRDYV SQFEGSALGK QLNLKLLDNW DSVTSTFSKL REQLGPVTQE FWDNLEKETE GLRQEMSKD LEEVKAKVQP YLDDFQKKWQ EEMELYRQKV EPLRAELQEG ARQKLHELQE KLSPLGEEMR DRARAHVDAL R THLAPYSD ELRQRLAARL EALKENGGAR LAEYHAKATE HLSTLSEKAK PALEDLRQGL LPVLESFKVS FLSALEEYTK KL NTQ

UniProtKB: Apolipoprotein A-I

Experimental details

Structure determination

• Method: cryo EM
• Processing: helical reconstruction
• Aggregation state: filament

Sample preparation

• Buffer: pH: 7 / Details: H2O containing 5 mM EDTA
• Grid: Model: 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. / Pretreatment - Atmosphere: AIR
• Vitrification: Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

Electron microscopy

• Microscope: TFS KRIOS
• Image recording: Film or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 16496 / Average exposure time: 5.0 sec. / Average electron dose: 40.0 e/Ų
• Electron beam: Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
• Electron optics: Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
• Experimental equipment: Model: Titan Krios / Image courtesy: FEI Company

Image processing

• Final reconstruction: Applied symmetry - Helical parameters - Δz: 4.85 Å; Applied symmetry - Helical parameters - Δ&Phi: -0.66 °; Applied symmetry - Helical parameters - Axial symmetry: C₁ (asymmetric); Resolution.type: BY AUTHOR / Resolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 165734
• CTF correction: Software - Name: CTFFIND / Details: RELION 4 built in CTFFIND / Type: NONE
• Startup model: Type of model: INSILICO MODEL; In silico model: initial model was generated using relion_helix_inimodel2d.
• Final angle assignment: Type: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)

Atomic model buiding 1

Initial model

PDB ID:

9pvy

Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model

• Refinement: Space: REAL / Protocol: RIGID BODY FIT

Output model

PDB-9pvz:
Cryo-EM structure of cardiac amyloid fibril from a variant apolipoprotein A-I R173P amyloidosis patient