Abstract
Numerous mutations in the corneal protein TGFBIp lead to opaque extracellular deposits and corneal dystrophies (CDs). Here we elucidate the molecular origins underlying TGFBIp's mutation-induced increase in aggregation propensity through comprehensive biophysical and bioinformatic analyses of mutations associated with every major subtype of TGFBIp-linked CDs including lattice corneal dystrophy (LCD) and three subtypes of granular corneal dystrophy (GCD 1-3). LCD mutations at buried positions in the C-terminal Fas1-4 domain lead to decreased stability. GCD variants show biophysical profiles distinct from those of LCD mutations. GCD 1 and 3 mutations reduce solubility rather than stability. Half of the 50 positions within Fas1-4 most sensitive to mutation are associated with at least one known disease-causing mutation, including 10 of the top 11 positions. Thus, TGFBIp aggregation is driven by mutations that despite their physico-chemical diversity target either the stability or solubility of Fas1-4 in predictable ways, suggesting straightforward general therapeutic strategies.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Molecular Biology |
Vol/bind | 430 |
Nummer | 8 |
Sider (fra-til) | 1116-1140 |
Antal sider | 25 |
ISSN | 0022-2836 |
DOI | |
Status | Udgivet - 13 apr. 2018 |