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Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1021/acs.biochem.7b00668
Forlagets udgivne version
- Nadia Sukusu Nielsen
- Dennis Wilkens Juhl
- Ebbe Toftgaard Poulsen ,
- Marie V Lukassen, Danmark
- Emil Christian Poulsen
- Michael W Risør ,
- Carsten Scavenius
- Jan Johannes Enghild
Mutations in the transforming growth factor β-induced protein (TGFBIp) cause phenotypically diverse corneal dystrophies, where protein aggregation in the cornea leads to severe visual impairment. Previous studies have shown a relationship between mutant-specific corneal dystrophy phenotypes and the thermodynamic stability of TGFBIp. Using LC-MS/MS and NMR, we investigated correlations between the structural integrity of disease-related mutants of the fourth FAS1 domain (FAS1-4) and deamidation of TGFBIp residue Asn622. We observed a high rate of Asn622 deamidation in the A546D and A546D/P551Q FAS1-4 mutants that were both largely unstructured by NMR. Conversely, the more structurally organized A546T and V624M FAS1-4 mutants had reduced deamidation rates suggesting that a folded and stable FAS1-4 domain precludes Asn622 deamidation. Wild-type (WT), R555Q and R555W FAS1-4 mutants displayed very slow deamidation, which agrees with their similar and ordered NMR structures, where Asn622 is in a locked conformation. We confirmed the FAS1-4 mutational effect on deamidation rates in full-length TGFBIp mutants and found a similar ranking compared to the FAS1-4 domain alone. Consequently, the deamidation rate of Asn622 can be used to predict the structural effect of the many destabilizing/stabilizing mutations reported for TGFBIp. In addition, the deamidation of Asn622 may influence the pathophysiology of TGFBIp-induced corneal dystrophies.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Biochemistry |
| Vol/bind | 56 |
| Nummer | 49 |
| Sider (fra-til) | 6470–6480 |
| Antal sider | 11 |
| ISSN | 0006-2960 |
| DOI | |
| Status | Udgivet - 28 nov. 2017 |
Se relationer på Aarhus Universitet Citationsformater
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