A complex equilibrium among partially unfolded conformations in monomeric transthyretin
| Autor: | Xinyi Li, Seyyed Abolghasem Ghadami, Fabrizio Chiti, Francesco Bemporad, Stefano Gianni, Simona Conti, Cristina Cecchi, Joel N. Buxbaum |
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| Přispěvatelé: | Dipartimento di Scienze Biomediche Sperimentali e Cliniche 'Mario Serio', Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Chemistry [Cambridge, UK], University of Cambridge [UK] (CAM), This study was supported by the Italian MIUR (FIRB Project RBFR109EOS and 'Programma per giovani ricercatori Rita Levi Montalcini 2012' to F.B. and Progetto di Interesse ‘Invecchiamento’ to S.G.), the Fondazione Cassa di Risparmio di Pistoia e Pescia (Project 2012.0266) (C.C. an S.C.), and Sapienza University of Rome (C26A13T9NB to S.G.)., Università degli Studi di Firenze [Firenze], Department of Biochemical Sciences, Università degli Studi di Roma 'La Sapienza' [Rome] - Réseau International des Instituts Pasteur - Institut Pasteur - Fondation Cenci Bolognetti, Department of Chemistry (Cambridge, UK), University of Cambridge (UK) |
| Rok vydání: | 2014 |
| Předmět: |
endocrine system
Protein Denaturation Protein Folding Proline Protein Conformation MESH: Protein Folding Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine MESH: Protein Conformation Isomerism [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Isomerism Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology 030304 developmental biology Protein Unfolding 0303 health sciences MESH: Humans MESH: Proline biology MESH: Kinetics MESH: Protein Multimerization Transferrin nutritional and metabolic diseases Transthyretin Kinetics Monomer chemistry MESH: Protein Unfolding Biophysics biology.protein MESH: Protein Denaturation Protein Multimerization 030217 neurology & neurosurgery MESH: Transferrin |
| Zdroj: | Biochemistry Biochemistry, American Chemical Society, 2014, 53 (27), pp.4381-92. ⟨10.1021/bi500430w⟩ Biochemistry, American Chemical Society, 2014, 53 (27), pp.4381-92. <10.1021/bi500430w> |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi500430w⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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