Probing the Hidden Sensitivity of Intrinsically Disordered Proteins to Their Chemical Environment

Abstract

Intrinsically disordered protein-regions (IDRs) play pivotal roles in signaling and regulatory pathways. A low number of intramolecular bonds and a high degree of surface area exposure make IDRs highly sensitive to changes in their surrounding solution, a situation that can be imagined as a constantly evolving “tug-of-war” between intramolecular and protein-solution interactions. Despite the vital importance of IDRs to cellular function, how they respond to fluctuations in the chemically dynamic cellular environment has not been thoroughly studied. To investigate changes in IDR structure in response to changing chemical surroundings, we developed a FRET-based high-throughput approach. We have used this approach, which we call “solution-space scanning,” to test four naturally occurring IDRs and three sequence scrambles of a naturally occurring IDR in over 180 biologically-compatible solution conditions. We found each sequence to have its own unique set of concentration-dependent responses to different solutes, which we term the sequence's “solution-space fingerprint.” We see that these fingerprints depend on IDR sequence and amino acid composition, but not on length. In live cells, using the same FRET constructs, the four naturally occurring IDRs showed global dimension trends in line with our high-throughput in vitro assay results. Our results underline the idea that IDRs must be understood not only in terms of their sequence, but also in the context of their environment. Based on these findings, we propose a general mechanism by which IDRs are able to function as sensors and actuators within cells.