Transthyretin Stabilizers: Preventing Amyloidosis

Abstract

Amyloidosis, a disease caused by aggregation of misfolded protein, affects millions of people. Deposition of aggregates interferes with normal function of organs and is sometimes caused by mutant forms of transthyretin (TTR), a protein found in blood and cerebrospinal fluid. Wild‐type TTR is a homotetramer that carries thyroxine (T4), a hormone that regulates metabolism. The tetramer arrangement forms a central channel which contains binding sites for T4. One point mutation responsible for V122I is amyloidogenic and common in African Americans (4% allele frequency). This substitution likely causes destabilization of TTR's native conformation, promoting dissociation to partially unfolded monomers. The monomers aggregate to form insoluble amyloid fibrils that are deposited in the heart. Valine and isoleucine, both hydrophobic amino acids, differ only by one methyl group; how this small alteration causes cardiac amyloidosis is unclear. T4 analog diflunisal, previously used to treat the disease, inhibits the vital enzyme cyclooxygenase. The Governor's Academy SMART (Students Modeling a Research Topic) team designed a model using 3D printing technology to highlight important structural features of TTR. A thorough understanding of the T4 binding site within TTR will allow design of effective kinetic stabilizers. Supported by a grant from NIH‐SEPA.