title: Trans-suppression of misfolding in an amyloid disease.
abstract: The transthyretin (TTR) amyloid diseases, representative of numerous misfolding disorders, are of considerable interest because there are mutations that cause or suppress disease. The Val30 --> Met30 (V30M) TTR mutation is the most prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas a Thr119 --> Met119 (T119M) mutation on the second TTR allele protects V30M carriers from disease. Here, we show that the incorporation of one or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation. Dissociation is required for amyloid formation, so these findings provide a molecular explanation for intragenic trans-suppression of amyloidosis. The data also suggest a potential therapeutic strategy, provide insight into tissue-specific deposition and amyloid composition, and support the validity of the amyloid hypothesis in human disease.
authors.affiliation: Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road BCC265, La Jolla, CA 92037, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hammarström
authors.forename: F
authors.initials: F
authors.lastname: Schneider
authors.forename: J W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000483:Alleles; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D017772:Amyloid Neuropathies / Q000235:genetics* / Q000378:metabolism; D001704:Biopolymers / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D021122:Protein Subunits; D012995:Solubility; D013489:Suppression, Genetic; D013816:Thermodynamics; D014170:Transformation, Genetic
chemical_list: D000682:Amyloid; D001704:Biopolymers; D011228:Prealbumin; D021122:Protein Subunits