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- EMDB-63849: Fibril structure of human alphaA-crystallin with pathogenic mutat... -

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Basic information

Entry
Database: EMDB / ID: EMD-63849
TitleFibril structure of human alphaA-crystallin with pathogenic mutation R116C
Map data
Sample
  • Complex: Amyloid fibrils formed by alpha A crystallin R116C
    • Protein or peptide: Alpha-crystallin A chain
Keywordscrystallin / amyloid / cryo-EM / cataract / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of intracellular transport / embryonic camera-type eye morphogenesis / apoptotic process involved in morphogenesis / lens fiber cell morphogenesis / tubulin complex assembly / structural constituent of eye lens / lens development in camera-type eye / response to UV-A / microtubule-based process / visual perception ...negative regulation of intracellular transport / embryonic camera-type eye morphogenesis / apoptotic process involved in morphogenesis / lens fiber cell morphogenesis / tubulin complex assembly / structural constituent of eye lens / lens development in camera-type eye / response to UV-A / microtubule-based process / visual perception / actin filament organization / mitochondrion organization / response to hydrogen peroxide / unfolded protein binding / response to heat / protein refolding / positive regulation of cell growth / response to hypoxia / protein stabilization / negative regulation of gene expression / negative regulation of apoptotic process / structural molecule activity / protein-containing complex / nucleoplasm / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Alpha-crystallin, N-terminal / Alpha crystallin A chain, N terminal / Alpha crystallin/Small heat shock protein, animal type / Hsp20/alpha crystallin family / Small heat shock protein (sHSP) domain profile. / Alpha crystallin/Hsp20 domain / HSP20-like chaperone
Similarity search - Domain/homology
Alpha-crystallin A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsCao Q / Song M
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Commun Chem / Year: 2025
Title: Cryo-EM structure of amyloid fibrils formed by full-length human αA-crystallin with pathogenic mutation R116C.
Authors: Meinai Song / Jianting Han / Qin Cao /
Abstract: The aggregation of crystallin proteins in human lens is the primary cause of cataracts, a disease that leads to blindness of tens of millions of people worldwide. Understanding the molecular ...The aggregation of crystallin proteins in human lens is the primary cause of cataracts, a disease that leads to blindness of tens of millions of people worldwide. Understanding the molecular architectures of these aggregated crystallin proteins can facilitate the development of therapeutic drugs to treat cataract without surgery. In this study, we prepared two types of crystallin fibrils, thick and thin, using recombinant human αA-crystallin harboring the disease-associated R116C mutation under neutral and acidic conditions, respectively. The structure of the thin fibrils was determined via cryo-EM at a resolution of 3.7 Å, whereas the thick fibrils appeared unsuitable for cryo-EM structure determination. Structure analysis suggests that the thin fibrils adopt a three-layered structure stabilized by extensive steric zipper interactions. The observation of aspartate and glutamate ladders stacking along the fibril axis is consistent with the preference for an acidic environment of the thin fibrils. Disease mutations on Arg49 and Arg54 appear to facilitate the fibril structure, suggesting the potential disease relevance of these fibrils. Taken together, our study provides the first near-atomic resolution structure of aggregated crystallin and may facilitate the future studies on the mechanism and therapeutic of cataracts.
History
DepositionMar 19, 2025-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBc / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_63849.map.gz / Format: CCP4 / Size: 12.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.932 Å
Density
Contour LevelBy AUTHOR: 2.4
Minimum - Maximum-6.6528983 - 8.594128
Average (Standard dev.)0.000000000003061 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-75-75-75
Dimensions150150150
Spacing150150150
CellA=B=C: 139.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Amyloid fibrils formed by alpha A crystallin R116C

EntireName: Amyloid fibrils formed by alpha A crystallin R116C
Components
  • Complex: Amyloid fibrils formed by alpha A crystallin R116C
    • Protein or peptide: Alpha-crystallin A chain

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Supramolecule #1: Amyloid fibrils formed by alpha A crystallin R116C

SupramoleculeName: Amyloid fibrils formed by alpha A crystallin R116C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-crystallin A chain

MacromoleculeName: Alpha-crystallin A chain / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.882264 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVTIQHPWF KRTLGPFYPS RLFDQFFGEG LFEYDLLPFL SSTISPYYRQ SLFRTVLDSG ISEVRSDRDK FVIFLDVKHF SPEDLTVKV QDDFVEIHGK HNERQDDHGY ISREFHCRYR LPSNVDQSAL SCSLSADGML TFCGPKIQTG LDATHAERAI P VSREEKPT SAPSS

UniProtKB: Alpha-crystallin A chain

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.79 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 58325
CTF correctionType: NONE
Segment selectionNumber selected: 3237381 / Software - Name: Topaz (ver. v0.2.5)
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-9u4l:
Fibril structure of human alphaA-crystallin with pathogenic mutation R116C

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