Key result
Viscoelastic linker properties and force-rate application govern the sequential unfolding hierarchy of polyproteins.
Why the study?
Although unfolding events in polyproteins are considered independent, history dependence of forced unfolding has been reported.
Demonstrates that viscoelasticity and force rate govern the sequential unfolding kinetics of polyproteins, challenging previous assumptions about stiffness and unfolding forces.
Challenges stiffness-centric unfolding models; leaves open validation in physiological cellular contexts.
Polyproteins are unique constructs, comprised of folded protein domains in tandem and polymeric linkers. These macromolecules perform under biological stresses by modulating their response through partial unfolding and extending. Although these unfolding events are considered independent, a history dependence of forced unfolding within polyproteins was reported. Here we measure the unfolding of single poly(I91) octamers, complemented with Brownian dynamics simulations, displaying increasing hierarchy in unfolding-foces, accompanied by a decrease in the effective stiffness. This counters the existing understanding that relates stiffness with variations in domain size and probe stiffness, which is expected to reduce the unfolding forces with every consecutive unfolding event. We utilize a simple mechanistic viscoelastic model to show that two effects are combined within a sequential forced unfolding process: the viscoelastic properties of the growing linker chain lead to a hierarchy of the unfolding events, and force-rate application governs the unfolding kinetics.
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Elias-Mordechai et al. (2020) studied this question. Sequential forced unfolding of polyproteins is governed by the viscoelastic properties of the growing linker chain and force-rate application, leading to a hierarchy of unfolding events.
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