Effect of Heparin on Protein Aggregation: Inhibition versus Promotion

Abstract

The effect of heparin on both native and denatured protein aggregation was investigated by turbidimetry and dynamic light scattering (DLS). Turbidimetric data show that heparin is capable of inhibiting and reversing the native aggregation of bovine serum albumin (BSA), β-lactoglobulin (BLG), and Zn−insulin at a pH near pI and at low ionic strength I; however, the results vary with regard to the range of pH, I, and protein−heparin stoichiometry required to achieve these effects. The kinetics of this process were studied to determine the mechanism by which interaction with heparin could result in inhibition or reversal of native protein aggregates. For each protein, the binding of heparin to distinctive intermediate aggregates formed at different times in the aggregation process dictates the outcome of complexation. This differential binding was explained by changes in the affinity of a given protein for heparin, partly due to the effects of protein charge anisotropy as visualized by electrostatic modeling. The heparin effect can be further extended to include inhibition of denaturing protein aggregation, as seen from the kinetics of BLG aggregation under conditions of thermally induced unfolding with and without heparin.

β-Lactoglobulin (BLG) binding to highly charged cationic polymer-grafted magnetic nanoparticles: Effect of ionic strength

“…Therefore a different mechanism likely accounts for the non-monotonic binding affinity. This result is also different from previous studies on TTMA-BLG binding [32] in which a monotonic dependence of the binding constant on the ionic strength was observed. It is believed that the surface properties should significantly influence the binding.…”

“…This is because of the very low concentration of BLG used during the titration as well as the suppression effect in the presence of polyelectrolyte grafted NPs. Previous studies indicate that the complexation usually take place prior to the BLG self-aggregation [32] . However, the results of DLS reveal a dramatically increase in complex diameter from 290 to 2590 nm at pH 3.8, while the turbidity increase is much less significant than DLS probably because DLS signal is more sensitive to the large particles even though the sample is measured at low concentrations.…”

Auto‐regulated Protein Assembly on a Supramolecular Scaffold

“…[3] Ligandinduced assembly can be regulated when high concentrations of ligand switch off oligomerization. [4][5][6] This phenomenon, similar to the bell-shaped dose-response curve of antibodyantigen interactions,h as been referred to as auto-regulation or auto-inhibition. [5][6][7] Taking inspiration from these biomolecular glues for protein oligomerization we describe herein an equivalent system based on asynthetic macrocycle.…”

Polyanion binding accelerates the formation of stable and low‐toxic aggregates of ALS‐linked SOD1 mutant A4V

“…Increasing evidence shows that heparin and nucleic acids, two types of the most essential polyanions for life, have a strong affinity for aggregation-prone pro-teins. 23,24 The affinity has often been found associated with the accelerated aggregation of proteins, including amyloid-b (Ab), prion protein (PrP), gelsolin, asynuclein, b2-microglobulin, transthyretin, and peptide hormones, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] which are implicated in a variety of diseases and biochemical processes. So far, it is unclear whether or not nucleic acids and heparin are involved in the formation of proteinaceous inclusions or deposits rich in SOD1 in cultured cells and animal models and in samples from ALS patients.…”