title: Thermodynamic study of transthyretin association (wild-type and senile forms) with heparan sulfate proteoglycan: pH effect and implication of the reactive histidine residue.
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.
authors.affiliation: Université de Franche-Comté, UFR SMP, EA 4662: Nanomedecine, Imagery Therapeupic Lab', Laboratoire de Chimie Analytique Bioanalytique et Physique, 25030, Besançon, cedex, France.
authors.forename: Ambre
authors.initials: A
authors.lastname: Geneste
authors.forename: Claire
authors.initials: C
authors.lastname: André
authors.forename: Nadine
authors.initials: N
authors.lastname: Magy-Bertrand
authors.forename: Lydie
authors.initials: L
authors.lastname: Lethier
authors.forename: Gharbi
authors.initials: G
authors.lastname: Tijani
authors.forename: Yves Claude
authors.initials: YC
authors.lastname: Guillaume
mesh_terms: D002851:Chromatography, High Pressure Liquid; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D019812:Heparan Sulfate Proteoglycans; D011228:Prealbumin; D006639:Histidine
keywords: amyloidogenic protein; heparan sulfate proteoglycan; transthyretin