Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder

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.

Evolutionary diversification of epidermal barrier genes in amphibians

“…Proline disrupts or terminates secondary structures in proteins, and glutamine and lysine are the targets of transglutamination, a process critical for epidermal cornification 4 . In addition, all three amino acids are associated with a high propensity to form disordered protein segments 30 , suggesting that SEDC proteins and the carboxy-terminal domain of SFTPs of caecilians are intrinsically disordered proteins, thus resembling their counterparts in mammals 31 – 33 . Sequence alignment showed similarities between SEDC proteins of caecilians and small proline-rich proteins (SPRRs) of mammals (Fig.…”

Clostridium botulinum C3bot mediated effects on cytokine-induced psoriasis-like phenotype in full-thickness skin model

“…Recently published data demonstrated that treatment of full-thickness skin model with cytokine mixture leads to a decrease in the thickness of the nucleated epidermis (Todorović et al 2022 ). In a long-term skin model with nanometer-thick fibronectin–gelatin-coated normal human dermal fibroblasts, a 5-day incubation with rhIL-17A causes a decrease in the thickness of the stratum granulosum (Singh et al 2020 ). Moreover, higher concentrations of cytokine mixture result in tissue disruption and detachment of the stratum corneum (Todorović et al 2022 ).…”

“…Additionally, this skin model mimics the route of exposure for dermally applied chemicals and therefore allows for testing conditions closer to the intended situation of use. Moreover, inflammatory stimuli could drive the development of the psoriasis-like phenotype in this model (Singh et al 2020 ). Psoriasis is a chronic inflammatory disease characterized by prominent epidermal proliferation and keratinocyte hyperplasia with altered differentiation and scale production.…”

BP180/Collagen XVII: A Molecular View

“…This hypothesis is supported by a new model incorporating a recently published flDPnn algorithm [37] which predicts protein and/or nucleic acid interactions with disordered regions of the ICD of BP180 (Figure 3c). It seems that the under-investigated field of intrinsic disorder in keratinocyte proteomes is gathering pace [38]. The implications of these intrinsic structural features of BP180 to its function as a component of HD and other structures are discussed in Section 4, Section 6, and Section 7 below.…”