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.

Comparative binding to DR4 and DR5 receptors of TRAIL and BNNTs/PAHE/mPEG‐DSPE/TRAIL nanoparticles

“…In this paper, we extended this result for the low‐affinity site DR4 and with BNNTs as nanocarriers. The role of His residues was previously described by our group for transthyretin and Aβ protein binding to heparan sulfate proteoglycan and nor‐NOHA/arginase complex formation . More recently, we demonstrated that the internalization of hTERT, a prototype shared tumor antigen that represents an attractive target for anticancer immunotherapy, by dendritic cells requires its interaction with heparan sulfate proteoglycans, this binding being enhanced with the protonation of His residues at acidic conditions .…”

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

“…As f, the volume phase ratio was a constant depending only on the geometrical characteristic of the column, DS˚* (with no unit) has the same variation versus pH as DS˚. As well, at a given temperature, the number of protons n released or gained by the buffer during the binding process was given by the slope of the curve lnk versus pH, that is, n = (dlnk/dpH) T /2.3 (21,22).…”

“…To demonstrate hTERT interaction with HSPG, we first used a biochromatographic approach based on HSPG column (21,22). As shown in Fig.…”