Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis
نویسندگان
چکیده
منابع مشابه
Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis.
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 bee...
متن کاملProgress in transthyretin fibrillogenesis research strengthens the amyloid hypothesis.
T amyloidoses are diseases of protein conformation, in which a particular soluble innocuous protein transforms and aggregates into an insoluble fibrillar structure that deposits in extracellular spaces of specific organs (reviewed in refs. 1–4). Organ dysfunction accompanies fibrillar deposition, and the amyloid hypothesis proposes a cause and effect relationship between deposition and dysfunct...
متن کاملA novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
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 protomer. Here, we investigate the mechanism of cleavage and release of the 49-127 fragment from the...
متن کاملKinetic assay for high-throughput screening of in vitro transthyretin amyloid fibrillogenesis inhibitors.
Stabilization of tetrameric transthyretin (TTR) by binding of small ligands is a current strategy aimed at inhibiting amyloid fibrillogenesis in transthyretin-associated pathologies, such as senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy (FAP). A kinetic assay is developed for rapid evaluation of compounds as potential in vitro inhibitors in a high-throughput screenin...
متن کاملSelection of Transthyretin Amyloid Inhibitors
Amyloidosis is a group of clinical disorders caused by the aggregation of specific proteins into abnormal extracellular deposits. Today, 31 different proteins have been linked to amyloid diseases including transthyretin-related amyloidosis (ATTR). ATTR occurs through the aggregation of either wild-type plasma protein transthyretin (TTR) or a mutated form. TTR is a homotetramer that under normal...
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ژورنال
عنوان ژورنال: Proceedings of the National Academy of Sciences
سال: 2014
ISSN: 0027-8424,1091-6490
DOI: 10.1073/pnas.1317488111