A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis

• Published in: EMBO 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
• Language: English
• 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

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...