Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep23836
Title: PH Induced Conformational Transitions in the Transforming Growth Factor ?-Induced Protein (TGF?IP) Associated Corneal Dystrophy Mutants
Authors: Murugan, E 
Venkatraman, A
Lei, Z
Mouvet, V
Rui Yi Lim, R
Muruganantham, N
Goh, E
Swee Lim Peh, G 
Beuerman, R.W 
Chaurasia, S.S
Rajamani, L
Mehta, J.S 
Keywords: amyloid protein
betaIG-H3 protein
recombinant protein
scleroprotein
transforming growth factor beta
amino acid sequence
cell survival
chemistry
congenital cornea dystrophy
cornea stroma
cytology
drug effects
Escherichia coli
fibroblast
gene expression
genetics
human
metabolism
molecular cloning
mutation
pathology
pH
primary cell culture
protein denaturation
protein domain
protein secondary structure
protein stability
Amino Acid Sequence
Amyloidogenic Proteins
Cell Survival
Cloning, Molecular
Corneal Dystrophies, Hereditary
Corneal Stroma
Escherichia coli
Extracellular Matrix Proteins
Fibroblasts
Gene Expression
Humans
Hydrogen-Ion Concentration
Mutation
Primary Cell Culture
Protein Denaturation
Protein Domains
Protein Stability
Protein Structure, Secondary
Recombinant Proteins
Transforming Growth Factor beta
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Murugan, E, Venkatraman, A, Lei, Z, Mouvet, V, Rui Yi Lim, R, Muruganantham, N, Goh, E, Swee Lim Peh, G, Beuerman, R.W, Chaurasia, S.S, Rajamani, L, Mehta, J.S (2016). PH Induced Conformational Transitions in the Transforming Growth Factor ?-Induced Protein (TGF?IP) Associated Corneal Dystrophy Mutants. Scientific Reports 6 : 23836. ScholarBank@NUS Repository. https://doi.org/10.1038/srep23836
Rights: Attribution 4.0 International
Abstract: Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-? induced protein (TGF?Ip). The 4 th-FAS1 domain of TGF?Ip harbors ?80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4 th-FAS1 domains of TGF?Ip carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from ?? conformation to ?-sheet oligomers. The ?-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that ?-oligomers of H572R were larger compared to R555W. The ?-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The ?-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/182487
ISSN: 2045-2322
DOI: 10.1038/srep23836
Rights: Attribution 4.0 International
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