The Scaffolding Subunit of PP2A is a Coherent Linear Elastic Object That Can Transmit Mechanical Information Along Its Length

Abstract

HEAT repeat protein PR65 is the scaffolding component of protein phosphatase PP2A, which has been implicated in tension sensing during chromosome segregation and in diverse other chromosomal processes. PR65 is composed exclusively of 15 HEAT repeats, i.e. pairs of anti-parallel alpha helices connected by short 1-3 residue turns, that stack in parallel to form a solenoid structure in which the packed helices form one continuous hydrophobic core. Molecular dynamics analysis reveals that tensile or compressive forces applied at the protein termini produce evenly-distributed shape changes (straightening/bending) via longitudinal redistribution of stress, with elastic coherence resulting from the continuous meshwork of van der Waals interactions created by the aligned helix/helix interfaces. At higher forces, fracturing occurs via loss of a specific helix/helix contact between adjacent repeats, accompanied by relaxation that spreads outward from the fracture site through the adjacent regions. Fracturing is nucleated by “flaws” resulting from atypical residues in inter-helix turns along the edges of the structure. Such flaw sites exhibit competition, such that only one of them fractures, as well as cooperation to create bounded regions of increased strain. Thus, PR65 is a coherent linear elastic object, capable of transducing mechanical information from one position along its length to another. We propose that HEAT repeat scaffolds, including PR65, exist to place bound components in mechanical linkage so that their promoted molecular reactions are sensitive to externally-imposed mechanical forces. More generally, since analogous elastic coherence should be present in many types of helical repeat proteins, cells may be filled with mechanically-tunable molecules, and mechanical stress may be a common currency for subcellular information transfer.