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Early Events in the Amyloid Formation of the A546T Mutant of Transforming Growth Factor β-Induced Protein in Corneal Dystrophies Compared to the Nonfibrillating R555W and R555Q Mutants.
- Source :
-
Biochemistry . 9/15/2015, Vol. 54 Issue 36, p5546-5556. 11p. - Publication Year :
- 2015
-
Abstract
- The human transforming growth factor β-induced protein (TGFBIp) is involved in several types of corneal dystrophies where protein aggregation and amyloid fibril formation severely impair vision. Most disease-causing mutations are located in the last of four homologous fasciclin-1 (FAS1) domains of the protein, and it has been shown that when isolated, the fourth FAS1 domain (FAS1-4) mimics the behavior of full-length TGFBIp. In this study, we use molecular dynamics simulations and principal component analysis to study the wild-type FAS1-4 domain along with three disease-causing mutations (R555W, R555Q, and A546T) to decipher any internal difference in dynamical properties of the domains that may explain their varied stabilities and aggregation properties. In addition, we use a protein-protein docking method in combination with chemical cross-linking experiments and mass spectrometry of the cross-linked species to obtain information about interaction faces between identical FAS1-4 domains. The results show that the pathogenic mutations A546T and R555W affect the packing in the hydrophobic core of FAS1-4 in different directions. We further show that the FAS1-4 monomers associate using their β-rich regions, consistent with peptides observed to be part of the amyloid fibril core in lattice corneal dystrophy patients. [ABSTRACT FROM AUTHOR]
- Subjects :
- *AMYLOID
*TRANSFORMING growth factor-beta induced protein
*CORNEAL dystrophies
Subjects
Details
- Language :
- English
- ISSN :
- 00062960
- Volume :
- 54
- Issue :
- 36
- Database :
- Academic Search Index
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 109947496
- Full Text :
- https://doi.org/10.1021/acs.biochem.5b00473