title: Transthyretin from discovery to now.
abstract: As introduction to the First International Congress on Transthyretin in Health and Disease, this lecture traces the origin of the subjectfrom the discovery in the 1950s that a serum protein migrating ahead of albumin in an electrical field binds the thyroid hormone, thyroxine. Early work defined the molecular and biological properties of thyroxine-binding prealbumin (TBPA). Its tetrameric structure, first recognized from a polymorphism in monkeys, was later elaborated by crystallographic studies, and the very different affinity of its two identical thyroxine-binding sites was explained by an allosteric effect upon occupation of the first site. The far higher concentration of TBPA in cerebrospinal fluid compared to blood was explained by the discovery, 30 years later, that TBPA is synthesized by cells of the choroid plexus, and its rapid turnover in the body made TBPA a convenient marker of malnutrition and chronic disease. Late in the 1960s it was learned that TBPA also carries vitamin A in the circulation by interacting with retinol-binding protein (RBP). TBPA then was renamed transthyretin (TTR), in recognition of its dual transport function, and it was shown that retinol-RBP-TTR interactions are mutually enhancing. Investigation of the molecular genetics of TTR began in 1980 and a large number of inherited variants were discovered in the ensuing years. Some affect thyroxine and/or RBP binding but the majority are associated with familial amyloidotic polyneuropathy. Seizing on this discovery, structural biologists are now investigating why mutated TTR changes from a compact, soluble molecule into a fibrillar, insoluble polymer, and how this pathological transformation might be prevented.
authors.affiliation: Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jacobr@bdg10.niddk.nih.gov
authors.forename: Jacob
authors.initials: J
authors.lastname: Robbins
mesh_terms: D003226:Congresses as Topic; D006801:Humans; D011228:Prealbumin / Q000378:metabolism / Q000502:physiology*; D012177:Retinol-Binding Proteins / Q000378:metabolism; D013975:Thyroxine-Binding Proteins / Q000378:metabolism
chemical_list: D011228:Prealbumin; D012177:Retinol-Binding Proteins; D013975:Thyroxine-Binding Proteins