Corneal dystrophy mutations drive pathogenesis by targeting TGFBIp stability and solubility in a latent amyloid-forming domain

Marcel Stenvang, Nicholas P Schafer, Kirsten Gade Malmos, Adriana-Michelle Wolf Pérez, Olatz Niembro, Pietro Sormanni, Rajiv Vaid Basaiawmoit, Gunna Christiansen, Maria Andreasen, Daniel E Otzen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
TidsskriftJournal of Molecular Biology
Vol/bind430
Nummer8
Sider (fra-til)1116-1140
Antal sider25
ISSN0022-2836
DOI
StatusUdgivet - 13 apr. 2018

Fingeraftryk

Dyk ned i forskningsemnerne om 'Corneal dystrophy mutations drive pathogenesis by targeting TGFBIp stability and solubility in a latent amyloid-forming domain'. Sammen danner de et unikt fingeraftryk.

Citationsformater