Early Events in the Amyloid Formation of the A546T Mutant of Transforming Growth Factor 尾-Induced Protein in Corneal Dystrophies Compared to the Nonfibrillating R555W and R555Q Mutants

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• 作者：Heidi Kolds酶 ; Ole Juul Andersen ; Camilla Lund Nikolajsen ; Carsten Scavenius ; Charlotte S. S酶rensen ; Jarl Underhaug ; Kasper Runager ; Niels Chr. Nielsen ; Jan J. Enghild ; Birgit Schi酶tt
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：September 15, 2015
• 年：2015
• 卷：54
• 期：36
• 页码：5546-5556
• 全文大小：655K
• ISSN：1520-4995

文摘

The human transforming growth factor 尾-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鈥損rotein 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 尾-rich regions, consistent with peptides observed to be part of the amyloid fibril core in lattice corneal dystrophy patients.