Affinage

KRT2

Keratin, type II cytoskeletal 2 epidermal · UniProt P35908

Round 2 corrected
Length
639 aa
Mass
65.4 kDa
Annotated
2026-04-28
41 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KRT2 is a type II intermediate filament keratin expressed in suprabasal differentiating keratinocytes that serves as a structural component of the epidermal cytoskeleton and the cornified cell envelope. It is covalently incorporated into the cornified envelope through transglutaminase-mediated isodipeptide cross-links with loricrin, filaggrin, and involucrin, thereby anchoring the intermediate filament network to the envelope scaffold (PMID:7543090, PMID:8999895). Dominant-negative mutations in KRT2 disrupt intermediate filament assembly in suprabasal keratinocytes and cause superficial epidermolytic ichthyosis, while somatic KRT2 mutations produce mosaic epidermolytic nevus in a cell-autonomous manner (PMID:26581228, PMID:33081034).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 1995 High

    Identifying KRT2 as a covalent component of the cornified cell envelope answered how the intermediate filament cytoskeleton is physically connected to the barrier structure of terminally differentiated epidermis.

    Evidence Proteinase K digestion of purified human cornified envelopes with peptide sequencing of isodipeptide cross-linked fragments identified KRT2–loricrin and KRT2–filaggrin cross-links

    PMID:7543090

    Open questions at the time
    • Specific cross-link sites on KRT2 itself were not mapped
    • The transglutaminase isoform(s) responsible for KRT2 cross-linking were not identified
    • Functional consequence of losing KRT2 cross-links was not tested
  2. 1997 High

    Demonstrating that involucrin bridges to KRT2 via transglutaminase-mediated bonds expanded the known CE scaffold architecture, establishing involucrin as an early scaffold connecting to the keratin network.

    Evidence Saponification and proteolytic digestion of purified CEs followed by amino acid sequencing identified involucrin Q288 as a cross-link acceptor for keratins including KRT2; immunogold EM confirmed structural localization

    PMID:8999895

    Open questions at the time
    • Whether KRT2 cross-linking to involucrin is required for CE mechanical integrity was not tested
    • Temporal order of KRT2 cross-linking relative to other CE components was not resolved
  3. 2016 Medium

    Identification of pathogenic KRT2 mutations in superficial epidermolytic ichthyosis families established that KRT2 is essential for normal suprabasal keratinocyte differentiation and that its disruption acts through a dominant-negative mechanism on intermediate filament assembly.

    Evidence Genetic sequencing of KRT2 in 26 keratinopathic ichthyosis families with clinical and histopathological correlation

    PMID:26581228

    Open questions at the time
    • No in vitro reconstitution of mutant KRT2 filaments to confirm dominant-negative disruption at the biochemical level
    • Genotype–phenotype correlations across the mutation spectrum remain incomplete
    • Whether compensatory upregulation of other type II keratins occurs was not assessed
  4. 2020 Medium

    Detection of a somatic KRT2 missense mutation in epidermolytic nevus demonstrated that KRT2 dysfunction is cell-autonomous and that mosaicism for KRT2 variants is sufficient for localized disease.

    Evidence Allele frequency quantification of KRT2 p.Asn186Asp in lesional skin (25%) versus blood (1.5%) confirming somatic origin

    PMID:33081034

    Open questions at the time
    • No functional assay of the p.Asn186Asp variant on filament assembly
    • Threshold allele frequency for phenotypic manifestation was not determined
    • Mechanism by which this specific variant disrupts intermediate filament architecture is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise structural basis of how KRT2 mutations disrupt intermediate filament assembly and the identity of the transglutaminase isoforms mediating KRT2 incorporation into the cornified envelope remain unresolved.
  • No high-resolution structural model of KRT2-containing intermediate filaments exists
  • In vitro reconstitution of disease-causing KRT2 mutants into filament assembly assays has not been reported
  • The functional redundancy between KRT2 and other suprabasal type II keratins (e.g., KRT1) is not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005856 cytoskeleton 3
Pathway
R-HSA-1266738 Developmental Biology 2
Partners
FLGIVLLOR

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Keratin 2e (KRT2) is covalently cross-linked via transglutaminase-induced isodipeptide bonds into the cornified cell envelope (CE) of human epidermis. Proteinase K digestion and peptide sequencing of purified CEs demonstrated that KRT2 (keratin 2e) forms cross-links with loricrin and filaggrin, placing KRT2 as a structural component anchoring the subjacent intermediate filament network to the CE scaffold. Proteinase K digestion of purified cornified cell envelopes from human foreskin epidermis followed by peptide sequencing of isodipeptide cross-linked fragments The Journal of Biological Chemistry High 7543090
1997 KRT2 (keratin 2e) is cross-linked to involucrin in the cornified cell envelope via transglutaminase-mediated isopeptide bonds. Amino acid sequencing of peptides released from saponified CEs identified specific glutamine residues in involucrin (Q288) that form cross-links to keratins including KRT2, demonstrating that involucrin serves as an early scaffold protein bridging to the keratin intermediate filament network. Saponification of purified cornified cell envelopes, proteolytic digestion, and amino acid sequencing of cross-linked peptides; immunogold electron microscopy The Journal of Biological Chemistry High 8999895
2006 KRT2 (previously called keratin 2e) was formally renamed under the new consensus mammalian keratin nomenclature. KRT2 is confirmed as a type II keratin expressed in suprabasal epidermis, forming part of the intermediate filament cytoskeleton in differentiating keratinocytes. Systematic genomic and proteomic analysis of the human keratin gene family with nomenclature revision The Journal of Cell Biology Medium 16831889
2016 Mutations in KRT2 cause superficial epidermolytic ichthyosis (SEI), an autosomal dominant keratinopathic ichthyosis. Novel pathogenic variants in KRT2 were identified, expanding the known mutation spectrum and establishing that KRT2 mutations disrupt epidermal differentiation in a dominant-negative manner consistent with disruption of intermediate filament assembly in suprabasal keratinocytes. Genetic sequencing of KRT2 in 26 families with keratinopathic ichthyoses; clinical and histopathological correlation Acta Dermato-Venereologica Medium 26581228
2020 A somatic missense mutation in KRT2 (p.Asn186Asp) was identified at 25% allelic frequency in lesional skin of a patient with epidermolytic nevus, with very low frequency (1.5%) in blood, establishing that somatic KRT2 mutations are sufficient to cause a mosaic epidermal differentiation disorder and that KRT2 functions in a cell-autonomous, dominant-negative manner in suprabasal keratinocytes. Molecular genetic testing of DNA from lesional skin and blood; allele frequency quantification confirming somatic origin International Journal of Molecular Sciences Medium 33081034
2016 KRT2 is expressed in alpaca melanocytes in vivo and in vitro, and transfection of KRT2 into alpaca melanocytes increased expression of the melanogenesis regulators MITF, TYR, and TYRP1, as well as melanin production, suggesting KRT2 participates in a regulatory pathway affecting melanogenesis. Immunohistochemistry, qPCR, Western blot, and transfection of KRT2 into alpaca melanocytes followed by measurement of melanogenic gene expression and melanin production Acta Histochemica Low 27265811

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2010 A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 565 20946988
2006 New consensus nomenclature for mammalian keratins. The Journal of cell biology 520 16831889
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
1995 The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope. The Journal of biological chemistry 452 7543090
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2019 Intrinsically Disordered Protein TEX264 Mediates ER-phagy. Molecular cell 296 31006538
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 292 32322062
2012 The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 272 23084401
2009 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research 237 19199708
2009 Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science signaling 207 19738201
1997 Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope. The Journal of biological chemistry 188 8999895
2017 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature communications 176 28685749
2007 14-3-3sigma controls mitotic translation to facilitate cytokinesis. Nature 173 17361185
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2010 Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription 161 21151833
2022 PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer. International journal of biological sciences 143 36147463
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2009 Charting the molecular network of the drug target Bcr-Abl. Proceedings of the National Academy of Sciences of the United States of America 137 19380743
2016 Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. Acta dermato-venereologica 48 26581228
2003 A small deletion hotspot in the type II keratin gene mK6irs1/Krt2-6g on mouse chromosome 15, a candidate for causing the wavy hair of the caracul (Ca) mutation. Genetics 44 14573483
2006 Morphologic and molecular characterization of two novel Krt71 (Krt2-6g) mutations: Krt71rco12 and Krt71rco13. Mammalian genome : official journal of the International Mammalian Genome Society 29 17143583
2020 First Case of KRT2 Epidermolytic Nevus and Novel Clinical and Genetic Findings in 26 Italian Patients with Keratinopathic Ichthyoses. International journal of molecular sciences 12 33081034
2016 The expression of KRT2 and its effect on melanogenesis in alpaca skins. Acta histochemica 10 27265811
1992 Genetic linkage analysis of the murine developmental mutant velvet coat (Ve) and the distal chromosome 15 developmental genes Hox-3.1, Rar-g, Wnt-1, and Krt-2. The Journal of experimental zoology 7 1379621
2022 Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2. International journal of molecular sciences 6 35887135
2021 Epidermolytic epidermal nevus caused by a somatic mutation in KRT2. Pediatric dermatology 2 33555633
2011 Genetic variation in the 5'UTR of the KRT2.13 gene of sheep. Animal science journal = Nihon chikusan Gakkaiho 1 22435621
2025 Tissue-specific expression, functional analysis, and polymorphism of the KRT2 gene in sheep horn. Genomics 0 39761764
2024 ABHD1 Facilitates Intermediate Filament-Mediated Endothelial Cell Chemotaxis by Regulating KRT1 and KRT2 in Diabetic Retinopathy. Journal of diabetes research 0 39619568