Revealing the Hidden Sensitivity of Intrinsically Disordered Proteins to their Chemical Environment

Abstract

Intrinsically disordered protein-regions (IDRs) make up roughly 30% of the human proteome and are central to a wide range of biological processes. Given a lack of persistent tertiary structure, all residues in IDRs are, to some extent, solvent exposed. This extensive surface area, coupled with the absence of strong intramolecular contacts, makes IDRs inherently sensitive to their chemical environment. We report a combined experimental, computational, and analytical framework for high-throughput characterization of IDR sensitivity. Our framework reveals that IDRs can expand or compact in response to changes in their solution environment. Importantly, the direction and magnitude of conformational change depend on both protein sequence and cosolute identity. For example, some solutes such as short polyethylene glycol chains exert an expanding effect on some IDRs and a compacting effect on others. Despite this complex behavior, we can rationally interpret IDR responsiveness to solution composition changes using relatively simple polymer models. Our results imply that solution-responsive IDRs are ubiquitous and can provide an additional layer of regulation to biological systems.

Intrinsically disordered protein biosensor tracks the physical-chemical effects of osmotic stress on cells

“…First, we performed all-atom Monte Carlo simulations to sample the conformational landscape of AtLEA4-5 under a wide range of solution conditions. This class of simulation, known as solution space (SolSpace) scanning, has been used to investigate the solution-protein interactions of dozens of IDRs (Holehouse and Sukenik, 2020; Moses et al, 2020). We used this method to exert a compacting force on a range of IDRs and compared the tendency of the different sequences to compact.…”

“…IDRs are key players in the process of liquid-liquid phase separation (LLPS), which is thought to mediate the formation of intracellular membraneless compartments such as the nucleolus (Shin and Brangwynne, 2017). Notably, the dynamic conformational structure of IDRs can be modulated by interaction with binding partners, posttranslational modifications, or changes in the chemical environment of the solution (Cuevas-Velazquez et al, 2016; Moses et al, 2020; Wright and Dyson, 2015). Despite this significant progress in understanding the functions of IDRs, their potential for building molecular tools such as biosensors has been largely overlooked.…”

“…The dataset of 70 other IDRs shown in Fig. 2A was obtained using the same methods, is publicly available on https://github.com/sukeniklab/HiddenSensitivity, and has been previously described (Moses et al, 2020). We analyzed the average radii of gyration of the simulated conformation ensembles using the MDTraj python library (McGibbon et al, 2015).…”

“…Conditions such as pH, temperature, redox state, and high osmolarity induce conformational changes in some IDRs (Theillet et al, 2014). Recent work shows that environmental sensitivity is a shared property of many IDRs (Holehouse and Sukenik, 2020; Moses et al, 2020). Furthermore, it has been proposed that the environmental sensitivity of IDRs could be used to regulate their activity, potentially allowing them to function as sensors of the environment (Cuevas-Velazquez and Dinneny, 2018; Scharwies and Dinneny, 2019; Yoo et al, 2019).…”

SWI/SNF senses carbon starvation with a pH-sensitive low complexity sequence

“…QLCs are present in glutamine-rich transactivation domains (30,31) some of which, including those found within SWI/SNF, may bind to transcription factors (32), or recruit transcriptional machinery (33)(34)(35). Intrinsically disordered regions lack a fixed three dimensional structure and have been proposed to be highly responsive to their solution environment (36,37). Moreover, the SWI/SNF QLCs contain multiple histidine residues.…”