This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Skoulakis, S. Articles by Goodfellow, J. M. Search for Related Content PubMed PubMed Citation Articles by Skoulakis, S. Articles by Goodfellow, J. M.

The pH-Dependent Stability of Wild-type and Mutant Transthyretin Oligomers

Department of Crystallography, Birkbeck College, University of London, London WC1E 7HX, UK

Correspondence: Address reprint requests to Spiros Skoulakis, Dept. of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK. Tel.: 0044-020-76316800; Fax: 0044-020-76316803; E-mail: s.skoulakis{at}mail.cryst.bbk.ac.uk.

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.