Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder
Abstract
:1. Introduction
1.1. Protein Intrinsic Disorder and Keratinocyte Biology
1.2. Epidermal Specialization and Keratinocyte-Related Protein Intrinsic Disorder
- Proteins of infecting bacterial and viral pathogens, the latter notably highlighting HPV oncoproteins;
- The dermal extracellular matrix protein elastin;
- Subdomains of familiar keratinocyte proteins, e.g., EGF receptor C-terminus and keratin N- and C-termini, for mediating protein–protein interactions in signaling and structural assembly, respectively;
- Specializations of non-human skin proteins for bio-reflectance or protection via skin-associated toxins in other organisms.
1.3. Proteins Encoded by Genes of the Human EDC Are Enriched for ID Traits
2. Bioinformatic Evaluations of Keratinocyte-Specific Proteins from the EDC Locus
2.1. Assessing Protein Intrinsic Disorder Encoded in the EDC
2.1.1. S100A Proteins
2.1.2. Loricrin, Involucrin, SPRR, and LCE
2.1.3. Profilaggrin and Related S100 Fused-Type Proteins (SFTPs)
2.2. Examining Intrinsic Disorder in the EDC Proteins of Non-Human Species
2.2.1. General EDC Protein Considerations across Species
2.2.2. SFTP Disorder: Frog Versus Human Sequence Considerations
2.2.3. SFTP Disorder and Liquid–Liquid Phase Separation: Frog Versus Human Sequence Evaluations
2.2.4. SFTP Liquid–Liquid Phase Separation: Further In Silico Assessments
3. Methodology
3.1. Literature Inquiry
3.2. Bioinformatics Assessments
4. Conclusions
4.1. Protein ID in the Keratinocyte Proteome Facilitates Cell Function
4.2. Investigations of Protein ID Synergize with Keratinocyte Biology
- Despite the few reports to date, the importance of IDPs in cutaneous biology can be expected to be the rule, not the exception. Intrinsic disorder is likely integral to the conformation and function not only of numerous endogenous keratinocyte proteins but also in therapeutically counteracting biofilm proteins of skin bacteria, e.g., Staphylococcus epidermidis, and oncogenic proteins of keratinocyte-tropic papilloma virus [25,29].
- Keratinocyte IDPs and proteins with extensive IDR, especially in upper epidermal strata, may be particularly favored in these superficial cells. Typical IDP qualities of being minimally affected (i.e., denatured) by harsh conditions or possessing “conformational plasticity” [9] could lend to understanding the resiliency of these cells as they are subjected to varying surface environmental assaults.
- The ID derived from numerous repeats enriched for disorder-promoting amino acids within keratinocyte-specific proteins may advantageously contribute to increased mammalian SFTP proteolytic sensitivity, efficiently yielding antimicrobial and hydrative peptides, respectively, from hornerin and filaggrin [5,8], and might be harnessed for clinical benefit by purposefully regulating the breakdown.
- Learning from human profilaggrin protein liquid–liquid phase separation for KG, it is worth conducting future direct biophysical experimentation with other keratinocyte-manifested structures such as cornified envelopes in the context of proteinaceous membraneless organelles (PMLO). This is especially appropriate in light of CE involucrin and loricrin self–self-protein interactions and their repeating amino acid motifs [74], which are biomolecular condensate- and PMLO-germane characteristics [75]. Strengthening this rationale is loricrin’s very favorable, pro-granule scoring in the LARKS and catGRANULE analysis. Investigation of keratinocyte sheath-like CE could add to the granule, speckle, and droplet categories of PMLO.
- Approximately 30 years of intense and elegant structural biology investigations of epithelial proteins such as keratins ([106] for review) have yielded a tremendous understanding regarding their function in tissue health and multiple disease states. We must now also face the fact that about one half of all eukaryotic proteins reside in a “dark proteome” [107] where conformational studies are often thwarted because of ID. As with Alice, we must reconsider what we think we know. It stands to reason that many keratinocyte-specific and -expressed proteins under current investigation, along with those of more established structure–function relationships, might be newly and revealingly viewed through the looking glass of ID. In this regard, keratinocyte normal physiology and pathophysiology can also be greatly affected by more broadly expressed IDPs, such as TNIP1, a repressor of inflammatory signaling, as we recently reported [53,108]. Additionally, there are the new lessons that the unique proteins of epidermal keratinocytes might provide to the IDP field. An integrated approach recently reviewed by Fuxreiter and colleagues [109] for membraneless organelles, protein–protein interaction, and phase separation in neurodegenerative disorders provides a roadmap for combining and applying ID computational and biophysical methodologies to other cell types. Such investigations of keratinocyte proteins could be a sea change moment for conformational understanding and subsequent translational cutaneous health benefits.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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1st Author | Journal Citation | Proteins Reported as IDPs or with IDR |
---|---|---|
Tuusa, J. | [6] | hemidesmosome protein BP180 |
Garcia Quiroz, F. | [7] | filaggrin in keratohyalin granules |
Shamilov, R. | [10] | nuclear receptor N-terminal AF-1 |
Levenson, R. | [11] | squid skin light-reflecting proteins |
Latendorf, T. | [5] | hornerin antimicrobial peptides |
Kurvits, L. | [12] | serum amyloid in skin biopsies |
Okamoto, K. | [13] | C-terminus of EGF-R |
Moens, M. | [14] | avian skin viral protein |
Gopalan, A. | [15] | TB proteins in skin lesions |
Uversky, V. | [9] | biofilms of pathogenic Staphylococcus epidermidis |
Singh, I. | [16] | C-terminus of EGF-R |
Rauscher, S. | [17] | skin ECM protein elastin |
Yarawsky, A. | [18] | biofilms of pathogenic Staphylococcus epidermidis |
Keppel, T. | [19] | C-terminus of EGF-R |
Muiznieks, L. | [20] | skin ECM protein elastin |
Levenson, R. | [21] | squid skin light-reflecting proteins |
Wang, B. | [22] | ubiquitin-conjugating enzyme |
Bray, D. | [23] | keratin N- and C-termini |
Kornreich, M. | [24] | keratin N- and C-termini |
Whelan, F. | [25] | biofilms of pathogenic Staphylococcus epidermidis |
Mukherjee, S. | [26] | proteins of cutaneous pathogen Leishmania major |
Joseph, S. | [27] | DNA-binding protein |
Richer, B. | [28] | skin ECM collagen subdomain |
Xue, B. | [29] | HPV oncoproteins |
Yates, C. | [30] | C-terminus of EGF-R |
Scorciapino, M. | [31] | frog skin antibacterial peptide |
Akinshina, A. | [32] | keratin N- and C-termini |
Graham, L. | [33] | frog skin-secreted adhesive protein |
Lewitzky, M. | [34] | C-terminus of EGF-R |
Shan, Y. | [35] | C-terminus of EGF-R |
Rauscher, S. | [36] | skin ECM protein elastin |
Lehoux, M. | [37] | HPV oncoproteins |
Majczak, G. | [38] | antimicrobial dermicidin protein |
Uversky, V. | [39] | HPV oncoproteins |
Trait | Hs PF1 | Hs PF2 | Xl SFTP2.S | Xl SFTP2.L | Xl SFTP1.S | Xl SFTP1.L |
---|---|---|---|---|---|---|
Sequence source | UniProt P20930 | UniProt Q5D862 | GenBank: OCT66701.1 | GenBank: OCT69537.1 [57] | [57] | GenBank: XP_018087213.1 |
# AA | 4061 | 2391 | 3075 | 2220 | 570 | 480 |
MW | 435 kDa | 248 kDa | 349 kDa | 249 kDa | 64 kDa | 54 kDa |
Theoretical pI | 9.24 | 8.45 | 8.77 | 8.03 | 8.65 | 6.90 |
ARG bias | 0.885 | 0.824 | 0.031 | 0.033 | 0.012 | 0.036 |
ARG % | 10.8 | 6.1% | 0.60 | 0.60 | 0.2% | 0.4% |
LYS % | 1.40 | 1.3% | 17.20 | 18.30 | 15.3% | 11.2% |
HIS % | 10.20 | 10.3 | 1.30 | 4.80 | 1.4% | 2.7% |
PONDR-FIT score w/N-term | 0.895 | 0.896 | 0.852 | 0.740 | 0.722 | 0.705 |
Aliphatic index | 19.76 | 15.97 | 15.62 | 26.91 | 62.39 | 49.65 |
SFTP | Propensity Score | Gly | Arg | Phe | SUM: Gly, Arg, Phe |
---|---|---|---|---|---|
Hs PF2 | 4.418 | 20.30% | 6.10% | 2.30% | 28.70% |
Hs PF1 | 3.553 | 12.80% | 10.80% | 0.60% | 24.20% |
Xl SFTP2.S | 2.019 | 3.50% | 0.60% | 0.60% | 4.70% |
Xl SFTP2.L | 1.179 | 0.80% | 0.60% | 0.90% | 2.30% |
Xl SFTP1.S | 0.561 | 2.50% | 0.20% | 0.70% | 3.40% |
Xl SFTP1.L | 0.063 | 2.50% | 0.40% | 1.50% | 4.40% |
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Shamilov, R.; Robinson, V.L.; Aneskievich, B.J. Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder. Int. J. Mol. Sci. 2021, 22, 7912. https://doi.org/10.3390/ijms22157912
Shamilov R, Robinson VL, Aneskievich BJ. Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder. International Journal of Molecular Sciences. 2021; 22(15):7912. https://doi.org/10.3390/ijms22157912
Chicago/Turabian StyleShamilov, Rambon, Victoria L. Robinson, and Brian J. Aneskievich. 2021. "Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder" International Journal of Molecular Sciences 22, no. 15: 7912. https://doi.org/10.3390/ijms22157912
APA StyleShamilov, R., Robinson, V. L., & Aneskievich, B. J. (2021). Seeing Keratinocyte Proteins through the Looking Glass of Intrinsic Disorder. International Journal of Molecular Sciences, 22(15), 7912. https://doi.org/10.3390/ijms22157912