Aggregation of Transforming Growth Factor β Induced Protein Studied by Protein-Protein Docking

Abstract

Transforming growth factor β induced protein (TGFBIp) is an extracellular matrix protein that has been linked to several types of corneal dystrophies. Nearly fifty percent of the mutations leading to corneal dystrophies affect two major single residue hotspots, namely R124 and R555, located in the first and the fourth FAS1 like domain of TGFBIp, respectively (1). The remaining mutations are primarily located in the fourth FAS1 like domain (FAS1-4). Three mutations in the FAS1-4 domain of TGFBIp are investigated in the present study: R555W, leading to granular corneal dystrophy; R555Q, leading to Thiel-Behnke corneal dystrophy; and A546T, leading to lattice corneal dystrophy. Of the three mutations, A546T is the only one resulting in deposits of amyloid fibrils in vivo and in vitro. The aim of this study is to investigate whether or not the three pathogenic mutations give rise to distinct association poses discerning between amorphous and amyloid phenotypes. Protein-Protein docking calculations have been performed using the docking algorithm DOCK/PIERR (2). Two highly abundant poses involving direct contact between the suspected fibrillating core regions of the FAS1-4 domain have been identified. Runager et al. has shown the A546T mutant to be the least stable of the three mutants (3). Combining the decreased stability with the docking poses could give an explanation to the amyloidogenic nature of the A546T mutant. 1. Munier et al. Invest. Ophthalmol. Vis. Sci. 2002, 4, 949-954. 2. Ravikant et al. Proteins 2010, 2, 400-419. 3. Runager et al. J. Biol. Chem 2011, 7, 4951-4958.