title: Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp.
abstract: Mutations in the transforming growth factor beta-induced (TGFBI) gene result in a group of hereditary diseases of the cornea that are collectively known as TGFBI corneal dystrophies. These mutations translate into amino acid substitutions mainly within the fourth fasciclin 1 domain (FAS1-4) of the transforming growth factor beta-induced protein (TGFBIp) and cause either amyloid or nonamyloid protein aggregates in the anterior and central parts of the cornea, depending on the mutation. The A546T substitution in TGFBIp causes lattice corneal dystrophy (LCD), which manifests as amyloid-type aggregates in the corneal stroma. We previously showed that the A546T substitution renders TGFBIp and the FAS1-4 domain thermodynamically less stable compared with the wild-type (WT) protein, and the mutant FAS1-4 is prone to amyloid formation in vitro. In the present study, we identified the core of A546T FAS1-4 amyloid fibrils. Significantly, we identified the Y571-R588 region of TGFBIp, which we previously found to be enriched in amyloid deposits in LCD patients. We further found that the Y571-R588 peptide seeded fibrillation of A546T FAS1-4, and, more importantly, we demonstrated that native TGFBIp aggregates in the presence of fibrils formed by the core peptide. Collectively, these data suggest an involvement of the Y571-R588 peptide in LCD pathophysiology.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Sørensen
authors.forename: Kasper
authors.initials: K
authors.lastname: Runager
authors.forename: Carsten
authors.initials: C
authors.lastname: Scavenius
authors.forename: Morten M
authors.initials: MM
authors.lastname: Jensen
authors.forename: Nadia S
authors.initials: NS
authors.lastname: Nielsen
authors.affiliation: ⊥Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus C, Denmark.
authors.forename: Gunna
authors.initials: G
authors.lastname: Christiansen
authors.affiliation: ⊥Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus C, Denmark.
authors.forename: Steen V
authors.initials: SV
authors.lastname: Petersen
authors.affiliation: ∥Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Niels Bohrs Allé 1, DK-5230 Odense M, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Karring
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Sanggaard
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
mesh_terms: D003317:Corneal Dystrophies, Hereditary / Q000378:metabolism; D003319:Corneal Stroma / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism*; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein