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 agonist-activated 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.
Highlights
Overview of Keratinocyte Differentiation and Key nuclear receptors (NR) PlayersThe upper, cellular layer of the skin, the epidermis, is a dynamic, renewing, stratified epithelium capable of protecting the underlying tissues from their desiccation as well as invasion and infiltration of surface microbes and toxins, respectively
Like the epidermal keratinocytes we highlighted above, are physiologically responsive to dietderived and endogenously-produced NR ligands integrally involved in their replication and differentiation
These combined approaches are increasing our overall comprehension of NR control of cell and organism physiology by offering new insight as to the amino-terminal conformational requirements for, and functional consequences of, post-translational modifications and interaction with NR coregulators
Summary
The upper, cellular layer of the skin, the epidermis, is a dynamic, renewing, stratified epithelium capable of protecting the underlying tissues from their desiccation as well as invasion and infiltration of surface microbes and toxins, respectively. More likely a true continuum than separate stages, Nuclear Receptor Research there are four histologically recognized epidermal cell layers [2]: basal, as defined by mitotic capacity and integrinmediated connection to the basal lamina; spinous, the upper layer characterized by formation of new and numerous desmosome cell-cell junctions; granular, with the hallmark of layer-specific keratohyalin granules and initiation of nuclear degradation; and squamous, at the interface with the environment, providing a physiologically inert layer made of highly protective, flattened cell products, with a totally degraded nucleus and filled with mostly insoluble, crosslinked proteins surrounded by extracellular lipids [3, 4] In addition to this classically recognized physical protection ability, the lower, metabolically active layers are being increasingly appreciated for their role as signal producers and mediators in inflammatory pathways [5, 6]. We note that these NR, while representative of those with epidermal keratinocyte relevance, are certainly not wholly exhaustive
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