biostudies-literatureFerguson JAAmerican Heart AssociationNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of General Medical SciencesNIGMS NIH HHS756-764https://www.ebi.ac.uk/biostudies/studies/S-EPMC8023301biostudies-literatureUnknown60(10)Misfolding and aggregation of transthyretin (TTR) are linked to amyloid disease. Amyloidosis occurs when the TTR homotetramer dissociates into aggregation-prone monomers that self-assemble into amyloid. In familial transthyretin amyloidosis, hereditary amino acid substitutions destabilize TTR and promote aggregation. In this work, we used ¹⁹F nuclear magnetic resonance (NMR) to determine the effect of mutations in the EF helix (Y78F, K80D, K80E, and A81T) and EF loop (G83R and I84S) on the aggregation kinetics and stability of the TTR tetramer and monomer. The EF region acts as a scaffold that stabilizes interactions in both the strong and weak dimer interfaces of the tetramer and is the site of a cluster of pathogenic mutations. K80D and K80E are non-natural mutants that destabBiochemistryThermodynamic Stability and Aggregation Kinetics of EF Helix and EF Loop Variants of Transthyretin.PMC8023301DK34909GM13169320POST35050060R35 GM131693R37 DK034909R01 DK124211R01 DK034909Wright PEDyson HJFerguson JASun XfalseThermodynamic Stability and Aggregation Kinetics of EF Helix and EF Loop Variants of Transthyretin.Misfolding and aggregation of transthyretin (TTR) are linked to amyloid disease. Amyloidosis occurs when the TTR homotetramer dissociates into aggregation-prone monomers that self-assemble into amyloid. In familial transthyretin amyloidosis, hereditary amino acid substitutions destabilize TTR and promote aggregation. In this work, we used ¹⁹F nuclear magnetic resonance (NMR) to determine the effect of mutations in the EF helix (Y78F, K80D, K80E, and A81T) and EF loop (G83R and I84S) on the aggregation kinetics and stability of the TTR tetramer and monomer. The EF region acts as a scaffold that stabilizes interactions in both the strong and weak dimer interfaces of the tetramer and is the site of a cluster of pathogenic mutations. K80D and K80E are non-natural mutants that destab2021-01-01T00:00:00Z2021 Mar2026-05-31T05:00:44.683Z2025-04-06T01:55:08.819ZS-EPMC80233013364521410.1021/acs.biochem.1c00073