A complex equilibrium among partially unfolded conformations in monomeric transthyretin.

Simona Conti (1) , Xinyi Li (2) , Stefano Gianni (3, 4) , Seyyed Abolghasem Ghadami (1) , Joel Buxbaum (2) , Cristina Cecchi (1) , Fabrizio Chiti (1) , Francesco Bemporad (1)

1 Dipartimento di Scienze Biomediche Sperimentali e Cliniche “Mario Serio”
2 Department of Molecular Medicine [Scripps Research Institute]
3 Department of Biochemical Sciences "Rossi Fanelli"
4 Department of Chemistry [Cambridge, UK]

Aggregation of transthyretin (TTR) is known to be linked to the development of systemic and localized amyloidoses. It also appears that TTR exerts a protective role against aggregation of the Aβ peptide, a process linked to Alzheimer's disease. In vitro, both processes correlate with the ability of TTR to populate a monomeric state, yet a complete description of the possible conformational states populated by monomeric TTR in vitro at physiological pH is missing. Using an array of biophysical methods and kinetic tests, we show that once monomers of transthyretin are released from the tetramer, equilibrium is established between a set of conformational states possessing different degrees of disorder. A molten globular state appears in equilibrium with the fully folded monomer, whereas an off-pathway species accumulates transiently during refolding of TTR. These two conformational ensembles are distinct in terms of structure, kinetics, and their pathways of formation. Further subpopulations of the protein fold differently because of the occurrence of proline isomerism. The identification of conformational states unrevealed in previous studies opens the way for further characterization of the amyloidogenicity of TTR and its protective role in Alzheimer's disease.

Domaines: Biochimie, Biologie Moléculaire

Simona Conti, Xinyi Li, Stefano Gianni, Seyyed Abolghasem Ghadami, Joel Buxbaum, et al.. A complex equilibrium among partially unfolded conformations in monomeric transthyretin.. Biochemistry, 2014, 53 (27), pp.4381-92. ⟨10.1021/bi500430w⟩. ⟨pasteur-01181239⟩