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- PDB-8hia: Structure of transforming growth factor beta induced protein (TGF... -

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Basic information

Entry
Database: PDB / ID: 8hia
TitleStructure of transforming growth factor beta induced protein (TGFBIp) G623R fibril
ComponentsTransforming growth factor-beta-induced protein ig-h3
KeywordsPROTEIN FIBRIL / Pathological fibrils / TGFBI related corneal dystrophy
Function / homology
Function and homology information


negative regulation of cell adhesion / extracellular matrix binding / extracellular matrix structural constituent / basement membrane / chondrocyte differentiation / collagen binding / cell adhesion molecule binding / extracellular matrix organization / visual perception / extracellular matrix ...negative regulation of cell adhesion / extracellular matrix binding / extracellular matrix structural constituent / basement membrane / chondrocyte differentiation / collagen binding / cell adhesion molecule binding / extracellular matrix organization / visual perception / extracellular matrix / trans-Golgi network / integrin binding / : / angiogenesis / cell population proliferation / cell adhesion / Amyloid fiber formation / extracellular space / extracellular exosome / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
TGF beta-induced protein/periostin / EMI domain / EMI domain profile. / : / Fasciclin domain / Four repeated domains in the Fasciclin I family of proteins, present in many other contexts. / FAS1 domain / FAS1 domain superfamily / FAS1/BIgH3 domain profile.
Similarity search - Domain/homology
Transforming growth factor-beta-induced protein ig-h3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.9 Å
AuthorsLow, J.Y.K. / Pervushin, K.
Funding support Singapore, 2items
OrganizationGrant numberCountry
Ministry of Education (MoE, Singapore)MOE2019-T3-1-012 Singapore
Ministry of Education (MoE, Singapore)RG28/19 Singapore
CitationJournal: Commun Biol / Year: 2023
Title: Release of frustration drives corneal amyloid disaggregation by brain chaperone.
Authors: Jia Yi Kimberly Low / Xiangyan Shi / Venkatraman Anandalakshmi / Dawn Neo / Gary Swee Lim Peh / Siew Kwan Koh / Lei Zhou / M K Abdul Rahim / Ketti Boo / JiaXuan Lee / Harini Mohanram / Reema ...Authors: Jia Yi Kimberly Low / Xiangyan Shi / Venkatraman Anandalakshmi / Dawn Neo / Gary Swee Lim Peh / Siew Kwan Koh / Lei Zhou / M K Abdul Rahim / Ketti Boo / JiaXuan Lee / Harini Mohanram / Reema Alag / Yuguang Mu / Jodhbir S Mehta / Konstantin Pervushin /
Abstract: TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ...TGFBI-related corneal dystrophy (CD) is characterized by the accumulation of insoluble protein deposits in the corneal tissues, eventually leading to progressive corneal opacity. Here we show that ATP-independent amyloid-β chaperone L-PGDS can effectively disaggregate corneal amyloids in surgically excised human cornea of TGFBI-CD patients and release trapped amyloid hallmark proteins. Since the mechanism of amyloid disassembly by ATP-independent chaperones is unknown, we reconstructed atomic models of the amyloids self-assembled from TGFBIp-derived peptides and their complex with L-PGDS using cryo-EM and NMR. We show that L-PGDS specifically recognizes structurally frustrated regions in the amyloids and releases those frustrations. The released free energy increases the chaperone's binding affinity to amyloids, resulting in local restructuring and breakage of amyloids to protofibrils. Our mechanistic model provides insights into the alternative source of energy utilized by ATP-independent disaggregases and highlights the possibility of using these chaperones as treatment strategies for different types of amyloid-related diseases.
History
DepositionNov 19, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Data collection / Data processing / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_reconstruction / em_entity_assembly_naturalsource
Item: _em_3d_reconstruction.num_particles / _em_entity_assembly_naturalsource.ncbi_tax_id / _em_entity_assembly_naturalsource.organism

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transforming growth factor-beta-induced protein ig-h3
B: Transforming growth factor-beta-induced protein ig-h3
C: Transforming growth factor-beta-induced protein ig-h3
D: Transforming growth factor-beta-induced protein ig-h3
E: Transforming growth factor-beta-induced protein ig-h3
F: Transforming growth factor-beta-induced protein ig-h3
G: Transforming growth factor-beta-induced protein ig-h3
H: Transforming growth factor-beta-induced protein ig-h3
I: Transforming growth factor-beta-induced protein ig-h3
J: Transforming growth factor-beta-induced protein ig-h3
K: Transforming growth factor-beta-induced protein ig-h3
L: Transforming growth factor-beta-induced protein ig-h3
M: Transforming growth factor-beta-induced protein ig-h3
N: Transforming growth factor-beta-induced protein ig-h3
O: Transforming growth factor-beta-induced protein ig-h3
P: Transforming growth factor-beta-induced protein ig-h3
Q: Transforming growth factor-beta-induced protein ig-h3
R: Transforming growth factor-beta-induced protein ig-h3
S: Transforming growth factor-beta-induced protein ig-h3
T: Transforming growth factor-beta-induced protein ig-h3


Theoretical massNumber of molelcules
Total (without water)50,95820
Polymers50,95820
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: NMR Distance Restraints, PDB code of monomer: 8HGA
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide
Transforming growth factor-beta-induced protein ig-h3


Mass: 2547.922 Da / Num. of mol.: 20
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBI / Production host: Escherichia coli (E. coli) / References: UniProt: Q15582

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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: Mutant of TGFBIp peptide derived from TGFBIp / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 21.43 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8 / Details: 20mM TRIS
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 8 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: NONE
Helical symmerty
IDImage processing-IDAngular rotation/subunit (°)Axial rise/subunit (Å)Axial symmetry
11-179.42.75C1
21-179.42.75C1
3D reconstructionResolution: 4.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48522 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0123580
ELECTRON MICROSCOPYf_angle_d1.1354920
ELECTRON MICROSCOPYf_dihedral_angle_d7.309480
ELECTRON MICROSCOPYf_chiral_restr0.063660
ELECTRON MICROSCOPYf_plane_restr0.018640

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