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Corneal Dystrophy Mutations Drive Pathogenesis by Targeting TGFBIp Stability and Solubility in a Latent Amyloid-forming Domain

Author:
Stenvang, Marcel, Schafer, Nicholas P., Malmos, Kirsten Gade, Pérez, Adriana-Michelle Wolf, Niembro, Olatz, Sormanni, Pietro, Basaiawmoit, Rajiv Vaid, Christiansen, Gunna, Andreasen, Maria, Otzen, Daniel E.
Source:
Journal of molecular biology 2018 v.430 pp. 1116-1140
ISSN:
0022-2836
Subject:
bioinformatics, cornea, mutation, pathogenesis, solubility
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.
Agid:
5925546