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- PDB-8hga: Monomer structure of transforming growth factor beta induced prot... -

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Basic information

Entry
Database: PDB / ID: 8hga
TitleMonomer structure 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 / response to stimulus / extracellular matrix structural constituent / basement membrane / chondrocyte differentiation / localization / collagen binding / visual perception / cell adhesion molecule binding ...negative regulation of cell adhesion / extracellular matrix binding / response to stimulus / extracellular matrix structural constituent / basement membrane / chondrocyte differentiation / localization / collagen binding / visual perception / cell adhesion molecule binding / extracellular matrix organization / extracellular matrix / trans-Golgi network / integrin binding / angiogenesis / collagen-containing extracellular matrix / 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. / FAS1 domain / FAS1 domain superfamily / Fasciclin domain / FAS1/BIgH3 domain profile. / Four repeated domains in the Fasciclin I family of proteins, present in many other contexts.
Similarity search - Domain/homology
Transforming growth factor-beta-induced protein ig-h3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLID-STATE NMR / molecular dynamics
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 14, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI

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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


Theoretical massNumber of molelcules
Total (without water)10,1924
Polymers10,1924
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2090 Å2
ΔGint-11 kcal/mol
Surface area10880 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 20back calculated data agree with experimental NOESY spectrum
RepresentativeModel #1lowest energy

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Components

#1: Protein/peptide
Transforming growth factor-beta-induced protein ig-h3 / Beta ig-h3 / Kerato-epithelin / RGD-containing collagen-associated protein / RGD-CAP


Mass: 2547.922 Da / Num. of mol.: 4 / Mutation: G623R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBI, BIGH3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15582

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Experimental details

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Experiment

ExperimentMethod: SOLID-STATE NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111anisotropic1NCA
171anisotropic1NCO
131anisotropic1DARR
141anisotropic1NCACX
151anisotropic1NCOCX
161anisotropic1CANCO

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Sample preparation

DetailsType: fiber
Contents: 10 mg/mL [U-100% 13C; U-100% 15N] TGFBIp G623R, ethanol/water
Label: 15_13C_sample / Solvent system: ethanol/water
SampleConc.: 10 mg/mL / Component: TGFBIp G623R / Isotopic labeling: [U-100% 13C; U-100% 15N]
Sample conditionsIonic strength: 20 mM / Label: conditions_1 / pH: 8 / Pressure: 1 atm / Temperature: 286 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE III / Manufacturer: Bruker / Model: AVANCE III / Field strength: 800 MHz

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Processing

NMR software
NameDeveloperClassification
TopSpinBruker Biospindata analysis
NMRFAM-SPARKYLee W, Tonelli M, Markley JLchemical shift assignment
CYANAGuntert, Mumenthaler and Wuthrichstructure calculation
GROMACSPaul Bauer, Berk Hess, Erik Lindahlrefinement
RefinementMethod: molecular dynamics / Software ordinal: 4
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: back calculated data agree with experimental NOESY spectrum
Conformers calculated total number: 20 / Conformers submitted total number: 10

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