Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

Mangione, P Patrizia, Porcari, Riccardo, Gillmore, Julian D, Pucci, Piero, Monti, Maria, Porcari, Mattia, Giorgetti, Sofia, Marchese, Loredana, Raimondi, Sara, Serpell, Louise C, Chen, Wenjie, Relini, Annalisa, Marcoux, Julien, Clatworthy, Innes R, Taylor, Graham W, Tennent, Glenys A, Robinson, Carol V, Hawkins, Phillip N, Stoppini, Monica, Wood, Stephen P, Pepys, Mark B and Bellotti, Vittorio (2014) Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis. Proceedings of the National Academy of Sciences, 111 (4). pp. 1539-1544. ISSN 0027-8424

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Abstract

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 wildtype 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Dementia Research Group
Depositing User: Louise Serpell
Date Deposited: 15 Aug 2018 08:31
Last Modified: 15 Aug 2018 08:35
URI: http://srodev.sussex.ac.uk/id/eprint/77853

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