First molecular characterization and immunolocalization of keratoepithelin in adult human skeletal muscle

Sciandra, Francesca; Morlacchi, Simona; Allamand, Valérie; Benedetti, Giacomo De; Macchia, Gianfranco; Petrucci, Tamara C.; Bozzi, Manuela; Brancaccio, Andrea

doi:10.1016/j.matbio.2007.12.003

Cited by 8 publications

(5 citation statements)

References 46 publications

(49 reference statements)

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“…Transforming growth factor β-induced protein (TGFBIp, UniProt entry Q15582) is a 72 kDa extracellular matrix protein encoded by the TGFBIp ( TGFBI ) gene . In addition to being expressed in a wide array of human tissues, − TGFBIp is a major constituent of the human cornea and is found throughout its various layers. , The protein consists of an N-terminal cysteine-rich domain (CRD), four consecutive fasciclin-1 (FAS1) domains, and an integrin-binding motif near its C-terminus . Recent analyses of the TGFBIp disulfide bond pattern have revealed disulfide bridges between the first FAS1 domain and both the CRD domain and the second FAS1 domain, whereas the third and fourth FAS1 domains (FAS1-4) appear to be less restrained …”

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confidence: 99%

Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein

et al. 2017

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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 liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance (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 as determined 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, 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 that of the FAS1-4 domain alone. Consequently, the deamidation rate of Asn622 can be used to predict the structural effect of the many destabilizing and/or stabilizing mutations reported for TGFBIp. In addition, the deamidation of Asn622 may influence the pathophysiology of TGFBIp-induced corneal dystrophies.

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confidence: 99%

Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein

et al. 2017

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“…Transforming growth factor β-induced protein (TGFBIp) also known as keratoepithelin and βig-h3 is a 72 kDa extracellular matrix (ECM) protein found in several tissues. − TGFBIp belongs to a group of homologous proteins that includes TGFBIp (Uniprot entry Q15582), Periostin (Uniprot entry Q15063), and the drosophila protein Midline fasciclin (Uniprot entry O61457) . They are all predicted to be composed of a putative NH 2 -terminal emilin (EMI) or cysteine-rich domain (CRD) and four fasciclin-1 domains .…”

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confidence: 99%

Disulfide Bond Pattern of Transforming Growth Factor β-Induced Protein

et al. 2016

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Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein composed of an NH-terminal cysteine-rich domain (CRD) annotated as an emilin (EMI) domain and four fasciclin-1 (FAS1-1-FAS1-4) domains. Mutations in the gene cause corneal dystrophies, a group of debilitating protein misfolding diseases that lead to severe visual impairment. Previous studies have shown that TGFBIp in the cornea is cross-linked to type XII collagen through a reducible bond. TGFBIp contains 11 cysteine residues and is thus able to form five intramolecule disulfide bonds, leaving a single cysteine residue available for the collagen cross-link. The structures of TGFBIp and its homologues are unknown. We here present the disulfide bridge pattern of TGFBIp, which was determined by generating specific peptides. These were separated by ion exchange followed by reversed-phase high-performance liquid chromatography and analyzed by mass spectrometry and Edman degradation. The NH-terminal CRD contains six cysteine residues, and one of these (Cys65) was identified as the candidate for the reducible cross-link between TGFBIp and type XII collagen. In addition, the CRD contained two intradomain disulfide bridges (Cys49-Cys85 and Cys84-Cys97) and one interdomain disulfide bridge to FAS1-2 (Cys74-Cys339). Significantly, this arrangement violates the predicted disulfide bridge pattern of an EMI domain. The cysteine residues in FAS1-3 (Cys473 and Cys478) were shown to form an intradomain disulfide bridge. Finally, an interdomain disulfide bridge between FAS1-1 and FAS1-2 (Cys214-Cys317) was identified. The interdomain disulfide bonds indicate that the NH terminus of TGFBIp (CRD, FAS1-1, and FAS1-2) adopts a compact globular fold, leaving FAS1-3 and FAS1-4 exposed.

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“…Transforming growth factor β-induced protein (TGFBIp) is secreted as a 68 kDa protein after cleavage of a signal peptide and is, as its name implies, upregulated by transforming growth factor β . The protein is found in several human tissues; − of these, the cornea has a particularly high abundance of TGFBIp, ranging from 1 to 37% (depending on the corneal layer) relative to total protein abundance . TGFBIp contains an N-terminal EMI domain, four consecutive and homologous fasciclin1 (Fas1) domains, and a C-terminal RGD sequence.…”

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Epigallocatechin Gallate Remodels Fibrils of Lattice Corneal Dystrophy Protein, Facilitating Proteolytic Degradation and Preventing Formation of Membrane-Permeabilizing Species

Stenvang

Christiansen²,

Otzen

2016

Biochemistry

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Lattice corneal dystrophy is associated with painful recurrent corneal erosions and amyloid corneal opacities induced by transforming growth factor β-induced protein (TGFBIp) that impairs vision. The exact mechanism of amyloid fibril formation in corneal dystrophy is unknown but has been associated with destabilizing mutations in the fourth fasciclin 1 (Fas1-4) domain of TGFBIp. The green tea compound epigallocatechin gallate (EGCG) has been found to inhibit fibril formation of various amyloidogenic proteins in vitro. In this study, we investigated the effect of EGCG as a potential treatment in lattice corneal dystrophy (LCD) using Fas1-4 with the naturally occurring LCD-inducing A546T mutation. A fewfold molar excess of EGCG was found to inhibit fibril formation in vitro by directing Fas1-4 A546T into stable EGCG-bound protein oligomers. Incubation with 2 molar equiv of EGCG led to a 4-fold reduction in the aggregates' membrane disruptive potential, potentially indicative of significantly lower cytotoxicity with regard to corneal erosions. EGCG did not induce oligomer formation by wild-type Fas1-4, indicating that treatment with EGCG would not interfere with the native function of the wild-type protein. Addition of EGCG to 10-day-old fibrils reduced fibril content in a dose-dependent manner. Proteinase K was found to reduce the light scattering of nontreated fibrils by 31% but reduced that of fibrils treated with 8 molar equiv of EGCG by 85%. This suggests that EGCG remodeling of fibril structure can facilitate aggregate removal by endogenous proteases and thus alleviate the protein deposits' light scattering symptoms.

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First molecular characterization and immunolocalization of keratoepithelin in adult human skeletal muscle

Cited by 8 publications

References 46 publications

Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein

Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein

Disulfide Bond Pattern of Transforming Growth Factor β-Induced Protein

Epigallocatechin Gallate Remodels Fibrils of Lattice Corneal Dystrophy Protein, Facilitating Proteolytic Degradation and Preventing Formation of Membrane-Permeabilizing Species

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