The life of proteins under mechanical force

Abstract

Although much of our understanding of protein folding comes from studies of isolated protein domains in bulk, in the cellular environment the intervention of external molecular machines is essential during the protein life cycle. During the past decade single molecule force spectroscopy techniques have been extremely useful to deepen our understanding of these interventional molecular processes, as they allow for monitoring and manipulating mechanochemical events in individual protein molecules. Here, we review some of the critical steps in the protein life cycle, starting with the biosynthesis of the nascent polypeptide chain in the ribosome, continuing with the folding supported by chaperones and the translocation into different cell compartments, and ending with proteolysis in the proteasome. Along these steps, proteins experience molecular forces often combined with chemical transformations, affecting their folding and structure, which are measured or mimicked in the laboratory by the application of force with a single molecule apparatus. These mechanochemical reactions can potentially be used as targets for fighting against diseases. Inspired by these insightful experiments, we devise an outlook on the emerging field of mechanopharmacology, which reflects an alternative paradigm for drug design.

Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays

“…α-synuclein) occurs in dependence on its energetic landscape, defined by the thermodynamic constrictions that force it to assume the conformation of the lowest free energy. Whereas protein folding is regulated mostly by chaperones [2,3], a class of proteins called intrinsically disordered proteins (IDPs, such as α-synuclein), which owns a low complexity region that may adopt an alternative, β-sheets enriched conformation [4][5][6][7], show poor binding features to chaperones [8][9][10][11]. IDPs may form fibrils and plaques [12], characterized by a β-sheet conformation with β-strands perpendicular to the length of the fibril, favoured by an exclusion of water from the inner core of the fibril and hydrophobic interactions.…”

Next Generation Methods for Single-Molecule Force Spectroscopy on Polyproteins and Receptor-Ligand Complexes

“…The purpose of this focused review is to highlight recent advances in AFM-based SMFS methodology that address the existing limitations and improve aspects such as sample throughput, sensitivity, reliability, and general robustness of the measurement. There are several recent reviews on related topics that overlap with the current review (Chen et al, 2015;Hughes and Dougan, 2016;Schönfelder et al, 2016aSchönfelder et al, , 2018Johnson and Thomas, 2018;Li and Zheng, 2018;Nathwani et al, 2018), and we regret that we were not able to include all the relevant work. We have organized the review into three sections.…”

Magnetic tweezers meets AFM: ultra-stable protein dynamics across the force spectrum

“…Proteins that participate in processes such as mechanotransduction, cell adhesion, or muscle contraction are exposed and carry out their function under force 1,2 . Mechanical loads induce conformational changes on these proteins, triggering downstream events like the recruitment of molecular partners 3 , the increase of intermolecular bond lifetimes 4 , or the delivery of mechanical work 5 .…”