The serine protease HtrA1 cleaves misfolded transforming growth factor β–induced protein (TGFBIp) and induces amyloid formation
| العنوان: | The serine protease HtrA1 cleaves misfolded transforming growth factor β–induced protein (TGFBIp) and induces amyloid formation |
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| المؤلفون: | Marie V. Lukassen, Henrik Vorum, Carsten Scavenius, Casper Bøjer Rasmussen, Kasper Runager, Michael W. Risør, Gunna Christiansen, Mette Richner, Emilie Hage Mogensen, Ebbe Toftgaard Poulsen, Nadia Sukusu Nielsen, Jan J. Enghild |
| المصدر: | Poulsen, E T, Nielsen, N S, Scavenius, C, Mogensen, E H, Risør, M W, Runager, K, Lukassen, M V, Rasmussen, C B, Christiansen, G, Richner, M, Vorum, H & Enghild, J J 2019, ' The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation ', The Journal of biological chemistry . https://doi.org/10.1074/jbc.RA119.009050Test Poulsen, E T, Nielsen, N S, Scavenius, C, Mogensen, E H, Risør, M W, Runager, K, Lukassen, M V, Rasmussen, C B, Christiansen, G, Richner, M, Vorum, H & Enghild, J J 2019, ' The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation ', The Journal of Biological Chemistry, vol. 294, no. 31, pp. 11817-11828 . https://doi.org/10.1074/jbc.RA119.009050Test Poulsen, E T, Nielsen, N S, Scavenius, C, Mogensen, E H, Risør, M W, Runager, K, Lukassen, M V, Rasmussen, C B, Christiansen, G, Richner, M, Vorum, H & Enghild, J J 2019, ' The serine protease HtrA1 cleaves misfolded transforming growth factor β-induced protein (TGFBIp) and induces amyloid formation ', Journal of Biological Chemistry, vol. 294, no. 31, pp. 11817-11828 . https://doi.org/10.1074/jbc.RA119.009050Test The Journal of Biological Chemistry |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Protein Folding, granular corneal dystrophy (GCD), Corneal dystrophy, SUSCEPTIBILITY, Biochemistry, Corneal Diseases, Cornea, BIGH3, chemistry.chemical_compound, transforming growth factor β–induced protein (TGFBIp), Transforming Growth Factor beta, Tandem Mass Spectrometry, protein misfolding, High-Temperature Requirement A Serine Peptidase 1/genetics, Chromatography, High Pressure Liquid, Aged, 80 and over, Extracellular Matrix Proteins, biology, Amyloidosis, amyloid, Molecular Bases of Disease, Serine Protease HTRA1, High-Temperature Requirement A Serine Peptidase 1, Peptides/analysis, Recombinant Proteins, Cell biology, PROTEOMICS, Thioflavin, Protein folding, Cornea/metabolism, Amyloid, BETA-IG-H3, corneal dystrophy, lattice corneal dystrophy (LCD), Extracellular Matrix Proteins/chemistry, high-temperature requirement protein A1 (HtrA1), Amyloid/metabolism, MECHANISMS, 03 medical and health sciences, Protein Domains, cornea, REVEALS, medicine, Humans, Recombinant Proteins/biosynthesis, Molecular Biology, Serine protease, HTRA1, IDENTIFICATION, eye disorder, 030102 biochemistry & molecular biology, MUTATIONS, protein turnover, Corneal Diseases/metabolism, protease, Cell Biology, medicine.disease, eye diseases, LATTICE, 030104 developmental biology, chemistry, proteolytic processing, Mutagenesis, Site-Directed, biology.protein, Eye disorder, Peptides, MATRIX, transforming growth factor beta-induced protein (TGFBIp), Transforming Growth Factor beta/chemistry |
| الوصف: | The serine protease high-temperature requirement protein A1 (HtrA1) is associated with protein-misfolding disorders such as Alzheimer's disease and transforming growth factor b-induced protein (TGFBIp)-linked corneal dystrophy. In this study, using several biochemical and biophysical approaches, including recombinant protein expression, LC-MS/MS and 2D-PAGE analyses and thioflavin-T (ThT) fluorescence assays for amyloid fibril detection, and FTIR assays, we investigated the role of HtrA1 both in normal TGFBIp turnover and in corneal amyloid formation. We show that HtrA1 can cleave wild-type TGFBIp but prefers amyloidogenic variants. Corneal TGFBIp is extensively processed in healthy people, resulting in C-terminal degradation products spanning the FAS1-4 domain of TGFBIp. We show here that HtrA1 cleaves the wild-type FAS1-4 domain only inefficiently, whereas the amyloidogenic FAS1-4 mutations transform this domain into a considerably better HTRA1 substrate. Moreover, HtrA1 cleavage of the mutant FAS1-4 domains generated peptides capable of forming in vitro amyloid aggregates. Significantly, these peptides have been previously identified in amyloid deposits in vivo, supporting the idea that HtrA1 is a causative agent for TGFBIp-associated amyloidosis in corneal dystrophy. In summary, our results indicate that TGFBIp is an HtrA1 substrate and that some mutations in the gene encoding TGFBIp cause aberrant HtrA1-mediated processing that results in amyloidogenesis in corneal dystrophies. |
| وصف الملف: | application/pdf |
| تدمد: | 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9f7b89321d2e2e3c4461f45a54e5e1d0Test https://doi.org/10.1074/jbc.ra119.009050Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9f7b89321d2e2e3c4461f45a54e5e1d0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219258 |
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