Corneal Dystrophy Mutations Drive Pathogenesis by Targeting TGFBIp Stability and Solubility in a Latent Amyloid-forming Domain. Issue 8 (13th April 2018)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Journal of molecular biology. Volume 430:Issue 8(2018)
• Page Start: 1116
• Page End: 1140
• Publication Date: 2018-04-13
• Subjects: ANS 1, 8-anilino-napthalene sulfonate -- CD corneal dystrophy -- DLS dynamic light scattering -- DSF differential scanning fluorimetry -- far-UV CD far-ultraviolet circular dichroism -- Fas1–4 4th fasciclin domain in TGFBIp -- GCD granular corneal dystrophy -- LCD lattice corneal dystrophy -- nsSNP non-synonymous single-nucleotide polymorphism -- SEC size exclusion chromatography -- TEM transmission electron microscopy -- ThT Thioflavin T -- WT wild type; corneal dystrophy -- protein aggregation -- TGFBIp -- disease-causing mutations -- molecular pathology; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.03.001
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical Abstract: Highlights: We have elucidated the molecular basis of TGFBIp-driven corneal dystrophies. Our conclusions are supported by a combination of biophysical experiments and computational analyses. Granular corneal dystrophies arise from a reduction in solubility of folded TGFBIp. Lattice corneal dystrophy is caused by destabilizing mutations. Ten of the 11 positions in Fas1-4 that are predicted to be the most mutation-sensitive are disease linked.