Thermodynamic study of transthyretin association (wild‐type and senile forms) with heparan sulfate proteoglycan: pH effect and implication of the reactive histidine residue |
| |
| Authors: | Ambre Geneste Claire André Nadine Magy‐Bertrand Lydie Lethier Gharbi Tijani Yves Claude Guillaume |
| |
| Affiliation: | 1. Université de Franche‐Comté, UFR SMP, EA 4662: Nanomedecine, Imagery Therapeupic Lab’, Laboratoire de Chimie Analytique Bioanalytique et Physique, Besan?on, cedex, France;2. Département de Médecine Interne, CHRU Besan?on, Besan?on, cedex, France;3. P?le Pharmacie, CHRU Besan?on, Besan?on, cedex, France |
| |
| Abstract: | The tetramer destabilization of transthyretin into monomers and its fibrillation are phenomena leading to amyloid deposition. Heparan sulfate proteoglycan (HSPG) has been found in all amyloid deposits. A chromatographic approach was developed to compare binding parameters between wild‐type transthyretin (wtTTR) and an amyloidogenic transthyretin (sTTR). Results showed a greater affinity of sTTR for HSPG at pH 7.4 compared with wtTTR owing to the monomeric form of sTTR. Analysis of the thermodynamic parameters showed that van der Waals interactions were involved at the complex interface for both transthyretin forms. For sTTR, results from the plot representing the number of protons exchanged vs pH showed that the binding mechanism was pH‐dependent with a critical value at a pH 6.5. This observation was due to the protonation of a histidine residue as an imidazolium cation, which was not accessible when TTR was in its tetrameric structure. At pH >6.5, dehydration at the binding interface and several contacts between nonpolar groups of sTTR and HSPG were also coupled to binding for an optimal hydrogen‐bond network. At pH <6.5, the protonation of the His residue from sTTR monomer when pH decreased broke the hydrogen‐bond network, leading to its destabilization and thus producing slight conformational changes in the sTTR monomer structure. Copyright © 2014 John Wiley & Sons, Ltd. |
| |
| Keywords: | amyloidogenic protein transthyretin heparan sulfate proteoglycan |
|
|
