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- PDB-8gbr: Cardiac amyloid fibrils extracted from a wild-type ATTR amyloidos... -

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Basic information

Entry
Database: PDB / ID: 8gbr
TitleCardiac amyloid fibrils extracted from a wild-type ATTR amyloidosis patient
ComponentsTransthyretin
KeywordsPROTEIN FIBRIL / Transthyretin / Amyloidosis / Systemic amyloidosis / ATTR / Cardiac
Function / homology
Function and homology information


Retinoid cycle disease events / thyroid hormone binding / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / Non-integrin membrane-ECM interactions / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation ...Retinoid cycle disease events / thyroid hormone binding / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / Non-integrin membrane-ECM interactions / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsNguyen, B.A. / Saelices, L.
Funding support United States, 2items
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: Commun Biol / Year: 2024
Title: Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.
Authors: Binh An Nguyen / Virender Singh / Shumaila Afrin / Preeti Singh / Maja Pekala / Yasmin Ahmed / Rose Pedretti / Jacob Canepa / Andrew Lemoff / Barbara Kluve-Beckerman / Pawel M Wydorski / ...Authors: Binh An Nguyen / Virender Singh / Shumaila Afrin / Preeti Singh / Maja Pekala / Yasmin Ahmed / Rose Pedretti / Jacob Canepa / Andrew Lemoff / Barbara Kluve-Beckerman / Pawel M Wydorski / Farzeen Chhapra / Lorena Saelices /
Abstract: ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv ...ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.
History
DepositionFeb 28, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.3Sep 18, 2024Group: Data collection / Database references / Category: citation_author / em_admin
Item: _citation_author.identifier_ORCID / _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)79,5255
Polymers79,5255
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transthyretin / ATTR / Prealbumin / TBPA


Mass: 15904.984 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Heart / Plasmid details: Transthyretin amyloidosis / Tissue: Cardiac / References: UniProt: P02766

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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: cardiac amyloid fibril of wild-type transthyretin amyloidosis
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Cellular location: extracellular / Organ: Heart / Tissue: Cardiac
Buffer solutionpH: 7 / Details: fibrils are in water
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Purified by water extraction
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: 295.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2300 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 4.98 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8243

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategoryDetails
1EMAN22.31particle selection
4RELION3.1CTF correctionCTFFIND-4.1
7Coot0.9.8.1model fitting
9RELION3.1initial Euler assignment
10RELION3.1final Euler assignment
11RELION3.1classification
12RELION3.13D reconstruction
13PHENIX20model refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -1.245 ° / Axial rise/subunit: 4.898 Å / Axial symmetry: C1
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50584 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 71.63 / Protocol: RIGID BODY FIT / Space: REAL / Target criteria: Cross-correlation coefficient
Details: Initial fitting was done using Coot with rigid body fit, then real space refinement for better fitting
Atomic model buildingPDB-ID: 8E7D

8e7d


Pdb chain-ID: A / Accession code: 8E7D / Details: Similar structure / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043715
ELECTRON MICROSCOPYf_angle_d0.5485055
ELECTRON MICROSCOPYf_dihedral_angle_d4.971500
ELECTRON MICROSCOPYf_chiral_restr0.05595
ELECTRON MICROSCOPYf_plane_restr0.007625

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