A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
Abstract The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 trun...
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Springer Nature
2015-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505357 |
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| author | Julien Marcoux P Patrizia Mangione Riccardo Porcari Matteo T Degiacomi Guglielmo Verona Graham W Taylor Sofia Giorgetti Sara Raimondi Sarah Sanglier‐Cianférani Justin LP Benesch Ciro Cecconi Mohsin M Naqvi Julian D Gillmore Philip N Hawkins Monica Stoppini Carol V Robinson Mark B Pepys Vittorio Bellotti |
| author_facet | Julien Marcoux P Patrizia Mangione Riccardo Porcari Matteo T Degiacomi Guglielmo Verona Graham W Taylor Sofia Giorgetti Sara Raimondi Sarah Sanglier‐Cianférani Justin LP Benesch Ciro Cecconi Mohsin M Naqvi Julian D Gillmore Philip N Hawkins Monica Stoppini Carol V Robinson Mark B Pepys Vittorio Bellotti |
| author_sort | Julien Marcoux |
| collection | DOAJ |
| description | Abstract The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied. |
| format | Article |
| id | doaj-art-73bd04162dae41c1a8592516fd43e2e6 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-73bd04162dae41c1a8592516fd43e2e62025-08-20T02:11:17ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-08-017101337134910.15252/emmm.201505357A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesisJulien Marcoux0P Patrizia Mangione1Riccardo Porcari2Matteo T Degiacomi3Guglielmo Verona4Graham W Taylor5Sofia Giorgetti6Sara Raimondi7Sarah Sanglier‐Cianférani8Justin LP Benesch9Ciro Cecconi10Mohsin M Naqvi11Julian D Gillmore12Philip N Hawkins13Monica Stoppini14Carol V Robinson15Mark B Pepys16Vittorio Bellotti17Department of Chemistry, University of OxfordWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonDepartment of Chemistry, University of OxfordWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonDepartment of Molecular Medicine, Institute of Biochemistry, University of PaviaDepartment of Molecular Medicine, Institute of Biochemistry, University of PaviaLaboratoire de Spectrométrie de Masse BioOrganique (LSMBO), University of Strasbourg UDSDepartment of Chemistry, University of OxfordInstitute of Nanoscience S3, Consiglio Nazionale delle RicercheDepartment of Physics, Informatics and Mathematics, University of Modena and Reggio EmiliaWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonDepartment of Molecular Medicine, Institute of Biochemistry, University of PaviaDepartment of Chemistry, University of OxfordWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College LondonAbstract The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.https://doi.org/10.15252/emmm.201505357amyloidmechano‐enzymatic cleavagetransthyretin |
| spellingShingle | Julien Marcoux P Patrizia Mangione Riccardo Porcari Matteo T Degiacomi Guglielmo Verona Graham W Taylor Sofia Giorgetti Sara Raimondi Sarah Sanglier‐Cianférani Justin LP Benesch Ciro Cecconi Mohsin M Naqvi Julian D Gillmore Philip N Hawkins Monica Stoppini Carol V Robinson Mark B Pepys Vittorio Bellotti A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis EMBO Molecular Medicine amyloid mechano‐enzymatic cleavage transthyretin |
| title | A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| title_full | A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| title_fullStr | A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| title_full_unstemmed | A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| title_short | A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| title_sort | novel mechano enzymatic cleavage mechanism underlies transthyretin amyloidogenesis |
| topic | amyloid mechano‐enzymatic cleavage transthyretin |
| url | https://doi.org/10.15252/emmm.201505357 |
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