Effect of environment and charge patterning on the dynamics of marginally disordered proteins.

Abstract

Intrinsically disordered proteins (IDPs) and proteins with long intrinsically disordered regions (IDRs) compose a large fraction of the proteome in all domains of life. Despite an extensive body of literature on “ordinary” disordered proteins—ones with high charge to hydropathy ratio—disordered proteins with lower charge to hydropathy ratio remain underinvestigated. To what extent do such “borderline” proteins compactify or perhaps even fold under physiological conditions? In addition, how does the patterning of charged residues in the primary structure of these IDPs affect the three-dimensional structure? Here we aim to characterize three proteins with various degrees of disorder in vitro and in cell using a suite of biophysical techniques. Our results show that the chain dimensions of all three proteins are sensitive to temperature, ionic strength, and crowder concentration in vitro and inside cells, as predicted from analytical and computational models. Moreover, we observe cooperative collapse for two of the three proteins, reminiscent of folding transitions of globular proteins. We further show that charge decoration is the primary predictor of IDP chain dimensions and models that rely solely on the polymer net charge fail to capture the relative chain dimensions of the mutants of the IDPs in our study.