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Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis.

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 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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Mangione PP,Porcari R,Gillmore JD,Pucci P,Monti M,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

doi

10.1073/pnas.1317488111

subject

Has Abstract

pub_date

2014-01-28 00:00:00

pages

1539-44

issue

eissn

0027-8424

issn

1091-6490

pii

1317488111

journal_volume

111

pub_type

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Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis.