Anion Shielding of Electrostatic Repulsions in Transthyretin Modulates Stability and Amyloidosis: Insight into the Chaotrope Unfolding Dichotomy
| Autor: | Jeffery W. Kelly, Xin Jiang, Per Hammarström, Songpon Deechongkit |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Anions
Models Molecular Guanidinium chloride Amyloid Protein Denaturation Protein Folding Macromolecular Substances Protein Conformation Static Electricity Mole fraction Biochemistry Protein Structure Secondary Potassium Chloride chemistry.chemical_compound Drug Stability Tetramer Humans Prealbumin Urea Denaturation (biochemistry) Guanidine Binding Sites biology Chemistry nutritional and metabolic diseases Amyloidosis Recombinant Proteins Folding (chemistry) Kinetics Thyroxine Transthyretin Chaotropic agent Crystallography Cross-Linking Reagents Amino Acid Substitution Glutaral Mutagenesis Site-Directed biology.protein |
| Zdroj: | Biochemistry. 40:11453-11459 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi010673+ |
| Popis: | The balance between stabilizing forces and the localized electrostatic repulsions destabilizing the transthyretin (TTR) tetramer is tunable via anion shielding. The two symmetrical anion interaction sites in TTR are comprised of residues Lys15 and Lys15' from opposing subunits on the periphery of the two thyroxine binding sites. These epsilon-ammonium groups repel one another and destabilize the tetramer, unless an appropriate anion is present, which stabilizes the tetramer. Chaotrope denaturation of TTR exhibits unusual behavior in that urea appears to be a stronger denaturant than GdmCl (guanidinium chloride), even though GdmCl is typically twice as powerful as a denaturant. The shift in the midpoint of the urea denaturation curve to higher concentrations as well as the increase in the mole fraction of tetramer that is highly resistant to denaturation with increasing KCl concentration provides strong evidence that anion shielding stabilizes the TTR tetramer. A consequence of tetramer stabilization is folding hysteresis, because the high GdmCl concentrations required to denature the anion-stabilized tetramer do not allow refolding of the unfolded monomers. The formation of amyloid fibrils by TTR requires that its normal tetrameric structure dissociate to alternatively folded monomers, a process mediated by acidification (pH 5-4). This process is inhibited by Cl(-) ions in a concentration-dependent fashion. Chloride ion may not be the relevant physiological TTR stability modulator, but it is the main focus of these studies explaining the hysteresis observed in the denaturation and refolding studies with GdmCl. |
| Databáze: | OpenAIRE |
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