Intrinsic Disorder in Nuclear Receptor Amino Termini: From Investigational Challenge to Therapeutic Opportunity

Abstract

Epidermal keratinocytes form an effective renewable barrier to surface assaults and desiccation of underlying tissues through a tightly controlled program of regeneration and terminal differentiation which is significantly impacted by the activity of several members of the nuclear receptor (NR) superfamily. As such, there is significant interest in physiological and pharmacological control of select NRs. NRs are usually considered quintessential examples of constrained structure-function relationships among protein families because of amino acid identity and sequence subserving physical requirements inherent to a relatively centrally-located DNA-binding domain and carboxyl-terminal ligand-recognition domain which together lead to agonistactivated gene expression. Nevertheless, across the superfamily the amino terminus of many NR is an often-critical contributor in degree of receptor-dependent transcriptional activity despite little in apparent sequence similarity that might be instructive in understanding this ability. By looking beyond shared strict amino acid sequence identity, a number of investigations are revealing the "unstructured"-function consequences of this disparity. Significant correlations between in silico and in vitro biophysical assessments are highlighting the shared trait of the unstructured nature or intrinsic disorder (ID) of NR amino termini and related functional consequences. Rather than the limited protein sequence variation-on-a-theme seen for zinc fingers (DNA binding) or a hydrophobic pocket (ligand binding), these amino-termini show sequence order diversity but often strikingly shared amino acid composition profiles not supporting a one-sequence-one-structure conformation. In this review, we look to integrate amino-termini ID reported in the literature, or predicted here, for select keratinocyte-expressed NR. As evidenced by success in drug targeting the amino-terminus of the androgen receptor, increased appreciation of amino-termini structure-or unstructure-might provide better understanding of NR function in general and possible future investigations on pharmacologic control over keratinocyte regeneration and/or differentiation.

IDPs and their complexes in GPCR and nuclear receptor signaling

“…A number of studies has shown that the NTD of NRs is not only critical for several aspects of NR action but also can be exploited as drug targets, thereby opening new opportunities for endocrine-based therapies. 266,267 Lack of significant sequence homology between NRs within the NTD also suggests that targeting this domain could give selective modulators of NRs, yielding fewer side effects. Traditional views of structural drug discovery would tend to consider such intrinsically disordered regions as unattractive targets due to their lack of structure and the concomitant lack of binding pockets for small molecules to interact.…”

Exploring the Functional Landscape of the p53 Regulatory Domain: The Stabilizing Role of Post-Translational Modifications

“…Unfortunately, IDRs are frequently under-represented by researchers in favor of more stable and structured regions of proteins. 36 Exploration of IDRs through biophysical techniques, such as nuclear magnetic resonance (NMR) 37 and small-angle X-ray scattering (SAXS), 38 yields significant insights into their dynamic properties, providing information on the average conformational state and the dynamics of IDRs. CryoEM 39 is potentially useful, but limited to singular static structures and cannot capture the inherent dynamic nature of IDRs.…”