title: The pH-dependent stability of wild-type and mutant transthyretin oligomers.
abstract: A reduction in pH is known to induce the disassociation of the tetrameric form of transthyretin and favor the formation of amyloid fibers. Using continuum electrostatic techniques, we calculate the titration curves and the stability of dimer and tetramer formation of transthyretin as a function of pH. We find that the tetramer and the dimer become less stable than the monomer as the pH is lowered. The free energy difference is 13.8 kcal/mol for dimer formation and 27 kcal/mol for tetramer formation, from the monomers, when the pH is lowered from 7 to 3.9. Similar behavior is observed for both the wild-type and the mutant protein. Certain residues (namely Glu-72, His-88, His-90, Glu-92, and Tyr-116), play an important role in the binding process, as seen by the considerable pK(1/2) change of these residues upon dimer formation.
authors.affiliation: Department of Crystallography, Birkbeck College, University of London, UK. s.skoulakis@mail.cryst.bbk.ac.uk
authors.forename: S
authors.initials: S
authors.lastname: Skoulakis
authors.forename: J M
authors.initials: JM
authors.lastname: Goodfellow
mesh_terms: D000682:Amyloid / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D003461:Crystallography / Q000379:methods*; D004355:Drug Stability; D004735:Energy Transfer; D006863:Hydrogen-Ion Concentration; D046911:Macromolecular Substances; D008958:Models, Molecular; D009154:Mutation; D011108:Polymers / Q000737:chemistry*; D011228:Prealbumin / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D000682:Amyloid; D046911:Macromolecular Substances; D011108:Polymers; D011228:Prealbumin