Abstract
Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here, we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of 'energetic frustration'. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.
Highlights
A cornerstone of biological regulation is the ability of proteins to tune their particular activities in response to the binding of specific ligands at distinct regulatory sites (Motlagh et al, 2014)
The similarity between the relative transcriptional activities of the different two-domain isoforms studied here and those of the full-length three-domain isoforms studied previously (Bender et al, 2013; Lu and Cidlowski, 2005) (Figure 1 and Figure 1—figure supplement 1a and b’’), suggests that the ligandbinding domain (LBD) affects the magnitude of activity enhancement (Godowski et al, 1987; Hollenberg and Evans, 1988), it does not appear to qualitatively impact the communication between the DNA-binding domain (DBD) and the N-terminal domain (NTD) in each isoform
The affinities of the isoforms for DNA vary, despite having identical DBDs, indicating that the NTD of each isoform differentially communicates with its respective DBD (Figure 1 and Figure 1—figure supplement 1c–e)
Summary
A cornerstone of biological regulation is the ability of proteins to tune their particular activities in response to the binding of specific ligands at distinct regulatory sites (Motlagh et al, 2014). Such tunability has been explained by the concerted (Monod et al, 1965) or sequential (Koshland et al, 1966) models of allosteric regulation, which describe the coupling between binding sites in terms of ligand-induced changes in the average structure of the protein. More recent studies reveal that allostery is not restricted to structured proteins. The mechanism by which ID proteins facilitate allostery is not known
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