Abstract
Epidermal keratinocyte proteins include many with an eccentric amino acid content (compositional bias), atypical ultrastructural fate (built-in protease sensitivity), or assembly visible at the light microscope level (cytoplasmic granules). However, when considered through the looking glass of intrinsic disorder (ID), these apparent oddities seem quite expected. Keratinocyte proteins with highly repetitive motifs are of low complexity but high adaptation, providing polymers (e.g., profilaggrin) for proteolysis into bioactive derivatives, or monomers (e.g., loricrin) repeatedly cross-linked to self and other proteins to shield underlying tissue. Keratohyalin granules developing from liquid–liquid phase separation (LLPS) show that unique biomolecular condensates (BMC) and proteinaceous membraneless organelles (PMLO) occur in these highly customized cells. We conducted bioinformatic and in silico assessments of representative keratinocyte differentiation-dependent proteins. This was conducted in the context of them having demonstrated potential ID with the prospect of that characteristic driving formation of distinctive keratinocyte structures. Intriguingly, while ID is characteristic of many of these proteins, it does not appear to guarantee LLPS, nor is it required for incorporation into certain keratinocyte protein condensates. Further examination of keratinocyte-specific proteins will provide variations in the theme of PMLO, possibly recognizing new BMC for advancements in understanding intrinsically disordered proteins as reflected by keratinocyte biology.
Highlights
We find that the human (Homo sapiens, Hs) loricrin and the published three chicken (Gallus gallus, Gg) homologues all share, for their full-length proteins (Figure 3a), a very high average disorder score of ≥ 0.840 (PONDR-FIT global score: Hs 0.840, Gg1 0.921, Gg2 0.864, Gg3 0.878)
Our analysis indicates these relatively minor cornified envelope (CE) proteins from the small proline-rich region (SPRR) and late cornified envelope (LCE) families will be characterized by extensive disorders
In addition to the SFTP ortholog presence or absence across species, gene representation in the epidermal differentiation complex (EDC) can vary in number, as we presented above for the CE protein loricrin, with one gene in the human EDC, and three genes in the corresponding chicken locus
Summary
In vitro, and in vivo analyses of intrinsically disordered proteins (IDPs) are expanding the appreciation [1,2] of their diverse and multiple roles as “hubs” or foci of intracellular signaling, as scaffolds for protein condensates, and in contributing to other distinctive functions because of their presence as a “conformational ensemble” rather than one fixed three-dimensional structure [3]. This unique conformational characteristic is a consequence of amino acid sequences featuring a biased residue composition with increased polar, charged, and structure-breaking residues as compared to compactionsupporting hydrophobic residues. Despite the importance of signaling hubs and protein scaffolds in the cell biology and differentiation of keratinocytes, we found few reports of purposeful IDP investigations in these cells or, more broadly, in epidermal biology
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