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- PDB-9u4l: Fibril structure of human alphaA-crystallin with pathogenic mutat... -

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Basic information

Entry
Database: PDB / ID: 9u4l
TitleFibril structure of human alphaA-crystallin with pathogenic mutation R116C
ComponentsAlpha-crystallin A chain
KeywordsPROTEIN FIBRIL / crystallin / amyloid / cryo-EM / cataract
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsCao, Q. / Song, M.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Alpha-crystallin A chain
A: Alpha-crystallin A chain
B: Alpha-crystallin A chain
C: Alpha-crystallin A chain
E: Alpha-crystallin A chain
F: Alpha-crystallin A chain


Theoretical massNumber of molelcules
Total (without water)119,2946
Polymers119,2946
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Alpha-crystallin A chain / Heat shock protein beta-4 / HspB4 / Heat shock protein family B member 4


Mass: 19882.264 Da / Num. of mol.: 6 / Mutation: R116C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRYAA, CRYA1, HSPB4 / Production host: Escherichia coli (E. coli) / References: UniProt: P02489
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 formed by alpha A crystallin R116C / Type: RIBOSOME / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 3500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazv0.2.5particle selection
2PHENIX1.20.1_4487:model refinement
13RELION43D reconstruction
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -1.79 ° / Axial rise/subunit: 4.78 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 3237381
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 58325 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033552
ELECTRON MICROSCOPYf_angle_d0.4454794
ELECTRON MICROSCOPYf_dihedral_angle_d4.446456
ELECTRON MICROSCOPYf_chiral_restr0.042522
ELECTRON MICROSCOPYf_plane_restr0.004612

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