Pressure-temperature folding landscape in proteins involved in neurodegenerative diseases and cancer

Abstract

High hydrostatic pressure (HHP) is a valuable tool to study processes such as protein folding, protein hydration and protein-protein interactions. HHP is a nondestructive technique because it reversibly affects internal cavities excluded from the solvent present in the hydrophobic core of proteins. HHP allows the solvation of buried amino acid side chains, thus shifting the equilibrium towards states of the studied molecule or molecular ensemble that occupy smaller volumes. HHP has long been used to dissociate multimeric proteins and protein aggregates and allows investigation of intermediate folding states, some of which are formed by proteins involved in human degenerative diseases, such as spongiform encephalopathies and Parkinson's disease, as well as cancer. When coupled with nuclear magnetic resonance and spectroscopic methods such as infrared and fluorescence spectroscopy, HHP treatment facilitates the understanding of protein folding and misfolding processes; the latter is related to protein aggregation into amyloid or amorphous species. In this review, we will address how HHP provides information about intermediate folding states and the aggregation processes of p53, which is related to cancer, and prion proteins, transthyretin and α-synuclein, which are related to human degenerative diseases.

Keywords: 1-anilino 8-naphthalene sulfonate; 4, 4′-bis(1-anilinonaphthalene 8-sulfonate); ANS; Amyloid; DA; Degenerative disease; FTIR; Fourier transform infrared; HHP; High pressure; I state; LB; Lewy bodies; NMR; PD; Parkinson's disease; PrP; Protein aggregation; Protein misfolding; TEM; TTR; alpha-synuclein; bis-ANS; dopamine; high hydrostatic pressure; intermediate state; nuclear magnetic resonance; p53; p53 tumor suppressor protein; prion protein; rPrP; recombinant prion protein; transmission electron microscopy; transthyretin; α-syn.