A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis

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 pro...

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Published inEMBO molecular medicine Vol. 7; no. 10; pp. 1337 - 1349
Main Authors Marcoux, Julien, Mangione, P Patrizia, Porcari, Riccardo, Degiacomi, Matteo T, Verona, Guglielmo, Taylor, Graham W, Giorgetti, Sofia, Raimondi, Sara, Sanglier‐Cianférani, Sarah, Benesch, Justin LP, Cecconi, Ciro, Naqvi, Mohsin M, Gillmore, Julian D, Hawkins, Philip N, Stoppini, Monica, Robinson, Carol V, Pepys, Mark B, Bellotti, Vittorio
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.10.2015
EMBO Press
Wiley Open Access
John Wiley & Sons, Ltd
Springer Nature
Subjects
Amyloid
Amyloid Neuropathies, Familial - etiology
Amyloid Neuropathies, Familial - metabolism
Amyloidogenesis
Amyloidosis
Binding sites
Biochemistry, Molecular Biology
Chromatography
EMBO16
Fibrillogenesis
Fluid flow
Heart
Humans
Life Sciences
mechano‐enzymatic cleavage
Mutation
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Peptides
Physiology
Prealbumin - chemistry
Prealbumin - metabolism
Proteins
Proteolysis
Research Article
Structural Biology
Transthyretin
transthyretin
mechano‐enzymatic cleavage
amyloid
transthyretin Subject Categories Genetics
mechano-enzymatic cleavage
Gene Therapy & Genetic Disease
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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. Synopsis Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease. Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment. These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis. TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant. Graphical Abstract Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
AbstractList 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. Synopsis Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease. Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment. These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis. TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant. Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
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. Synopsis Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease. Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment. These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis. TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant. Graphical Abstract Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
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.
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.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.
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.
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.
Author Degiacomi, Matteo T
Taylor, Graham W
Porcari, Riccardo
Sanglier‐Cianférani, Sarah
Naqvi, Mohsin M
Raimondi, Sara
Giorgetti, Sofia
Hawkins, Philip N
Gillmore, Julian D
Stoppini, Monica
Pepys, Mark B
Robinson, Carol V
Verona, Guglielmo
Cecconi, Ciro
Marcoux, Julien
Bellotti, Vittorio
Mangione, P Patrizia
Benesch, Justin LP
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  surname: Marcoux
  fullname: Marcoux, Julien
  organization: Department of Chemistry, University of Oxford, Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), University of Strasbourg UDS, CNRS, Institute of Pharmacology and Structural Biology (IPBS)
– sequence: 2
  givenname: P Patrizia
  surname: Mangione
  fullname: Mangione, P Patrizia
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
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  givenname: Riccardo
  surname: Porcari
  fullname: Porcari, Riccardo
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London
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  surname: Degiacomi
  fullname: Degiacomi, Matteo T
  organization: Department of Chemistry, University of Oxford
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  surname: Verona
  fullname: Verona, Guglielmo
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
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  surname: Taylor
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  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London
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  givenname: Sofia
  surname: Giorgetti
  fullname: Giorgetti, Sofia
  organization: Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
– sequence: 8
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  surname: Raimondi
  fullname: Raimondi, Sara
  organization: Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
– sequence: 9
  givenname: Sarah
  surname: Sanglier‐Cianférani
  fullname: Sanglier‐Cianférani, Sarah
  organization: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), University of Strasbourg UDS
– sequence: 10
  givenname: Justin LP
  surname: Benesch
  fullname: Benesch, Justin LP
  organization: Department of Chemistry, University of Oxford
– sequence: 11
  givenname: Ciro
  surname: Cecconi
  fullname: Cecconi, Ciro
  organization: Institute of Nanoscience S3, Consiglio Nazionale delle Ricerche, Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia
– sequence: 12
  givenname: Mohsin M
  surname: Naqvi
  fullname: Naqvi, Mohsin M
  organization: Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia
– sequence: 13
  givenname: Julian D
  surname: Gillmore
  fullname: Gillmore, Julian D
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London
– sequence: 14
  givenname: Philip N
  surname: Hawkins
  fullname: Hawkins, Philip N
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London
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  surname: Stoppini
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  organization: Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
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  givenname: Carol V
  surname: Robinson
  fullname: Robinson, Carol V
  organization: Department of Chemistry, University of Oxford
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  givenname: Vittorio
  surname: Bellotti
  fullname: Bellotti, Vittorio
  email: v.bellotti@ucl.ac.uk
  organization: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Department of Molecular Medicine, Institute of Biochemistry, University of Pavia
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26286619$$D View this record in MEDLINE/PubMed
https://hal.science/hal-02335545$$DView record in HAL
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Issue 10
Keywords transthyretin
mechano‐enzymatic cleavage
amyloid
transthyretin Subject Categories Genetics
mechano-enzymatic cleavage
Gene Therapy & Genetic Disease
Language English
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2015 The Authors. Published under the terms of the CC BY 4.0 license.
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content type line 14
content type line 23
These authors contributed equally to this work
Current address: CNRS, Institute of Pharmacology and Structural Biology (IPBS), Toulouse, France
ORCID 0000-0001-7829-5505
0000-0001-7321-7436
0000-0003-4013-4129
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Snippet The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits...
The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits...
The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49-127 transthyretin fragment in ex vivo deposits...
The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits...
The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits...
Abstract The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo...
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SubjectTerms Amyloid
Amyloid Neuropathies, Familial - etiology
Amyloid Neuropathies, Familial - metabolism
Amyloidogenesis
Amyloidosis
Binding sites
Biochemistry, Molecular Biology
Chromatography
EMBO16
Fibrillogenesis
Fluid flow
Heart
Humans
Life Sciences
mechano‐enzymatic cleavage
Mutation
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Peptides
Physiology
Prealbumin - chemistry
Prealbumin - metabolism
Proteins
Proteolysis
Research Article
Structural Biology
Transthyretin
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Title A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
URI https://link.springer.com/article/10.15252/emmm.201505357
https://onlinelibrary.wiley.com/doi/abs/10.15252%2Femmm.201505357
https://www.ncbi.nlm.nih.gov/pubmed/26286619
https://www.proquest.com/docview/2290057063
https://www.proquest.com/docview/1718907045
https://hal.science/hal-02335545
https://pubmed.ncbi.nlm.nih.gov/PMC4604687
https://doaj.org/article/73bd04162dae41c1a8592516fd43e2e6
Volume 7
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