Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis
| Autor: | Louise C. Serpell, Vittorio Bellotti, Innes R. Clatworthy, Julian D. Gillmore, Graham W. Taylor, Monica Stoppini, Philip N. Hawkins, Julien Marcoux, Maria Chiara Monti, Loredana Marchese, Sara Raimondi, Palma Mangione, Piero Pucci, Steve P. Wood, Carol V. Robinson, Mark B. Pepys, Annalisa Relini, Mattia Porcari, Sofia Giorgetti, Riccardo Porcari, Glenys A. Tennent, Wenjie Chen |
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| Přispěvatelé: | Istituto di Matematica Applicata e Tecnologie Informatiche (IMATI-CNR), Consiglio Nazionale delle Ricerche [Roma] (CNR), Istituto per la Protezione delle Piante (IPP), Laboratoire des Sciences de l'Ingénieur Appliquées à la Mécanique et au génie Electrique (SIAME), Université de Pau et des Pays de l'Adour (UPPA), Dept Mol Med, University of Pavia, Mangione, Pp, Porcari, R, Gillmore, Jd, Pucci, Pietro, Monti, Maria, Porcari, M, Giorgetti, S, Marchese, L, Raimondi, S, Serpell, Lc, Chen, W, Relini, A, Marcoux, J, Clatworthy, Ir, Taylor, Gw, Tennent, Ga, Robinson, Cv, Hawkins, Pn, Stoppini, M, Wood, Sp, Pepys, Mb, Bellotti, V. |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
endocrine system
Amyloid Proline Proteolysis Molecular Sequence Data Molecular Conformation macromolecular substances Protein aggregation Cleavage (embryo) Fibril Crystallography X-Ray 03 medical and health sciences 0302 clinical medicine medicine Serine Humans Prealbumin Amino Acid Sequence Peptide sequence ComputingMilieux_MISCELLANEOUS 030304 developmental biology 0303 health sciences Multidisciplinary medicine.diagnostic_test biology Chemistry Amyloidosis nutritional and metabolic diseases Fibrillogenesis Hydrogen Bonding Biological Sciences medicine.disease Molecular biology nervous system diseases Transthyretin [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Phenotype Biochemistry biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2014, 111 (4), pp.1539-1544. ⟨10.1073/pnas.1317488111⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1317488111⟩ |
| Popis: | The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis. |
| Databáze: | OpenAIRE |
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