Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 72, Issue 1, Pages 261-269Publisher
WILEY-LISS
DOI: 10.1002/prot.21919
Keywords
transthyretin; amyloid; aggregation; amyloid disease; unfolding
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Senile systemic amyloidosis (SSA) is caused by amyloid deposits of wildtype transthyretin in various organs. Amyloid deposits from SSA contain large amounts of the C-terminal-fragments starting near amino acid residue 50 as well as full-length transthyretin. Although a number of previous studies suggest the importance of the C-terminal fragments in the pathogenesis of SSA, little is known about the structure and aggregation properties of the C-terminal fragments of transthyretin. To understand the role of C-terminal fragments in SSA, we examined the effects of the truncation of the N-terminal portions on the structure and aggregation properties of wild-type transthyretin. The deletion mutant lacking 50 N-terminal residues was largely unfolded in terms of secondary and tertiary structure, leading to self-assembly into spherical aggregations under nearly physiological conditions. By contrast, the deletion mutant lacking 37 N-terminal residues did not have a strong tendency to aggregate, although it also adopted a largely unfolded conformation. These results suggest that global unfolding of transthyretin by proteolysis near amino acid residue 50 is an important step of self-assembly into aggregations in SSA.
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