Against the Rules: Human Keratin K80

Abstract

Of the 54 human keratins, five members have, at present, only been characterized at the gene level. In this study we have investigated the expression patterns of keratin K80, whose gene is located at the centromeric end of the type II keratin gene domain. K80 possesses a number of highly unusual properties. Structurally, it is distinctly closer to type II hair keratins than to type II epithelial keratins. Nonetheless, it is found in virtually all types of epithelia (stratified keratinizing/non-keratinizing, hard-keratinizing, as well as non-stratified tissues, and cell cultures thereof). This conspicuously broad expression range implies an unprecedented in vivo promiscuity of K80, which involves more than 20 different type I partners for intermediate filament (IF) formation. Throughout, K80 expression is related to advanced tissue or cell differentiation. However, instead of being part of the cytoplasmic IF network, K80 containing IFs are located at the cell margins close to the desmosomal plaques, where they are tightly interlaced with the cytoplasmic IF bundles abutting there. In contrast, in cells entering terminal differentiation, K80 adopts the "conventional" cytoplasmic distribution. In evolutionary terms, K80 is one of the oldest keratins, demonstrable down to fish. In addition, KRT80 mRNA is subject to alternative splicing. Besides K80, we describe a smaller but fully functional splice variant K80.1, which arose only during mammalian evolution. Remarkably, unlike the widely expressed K80, the expression of K80.1 is restricted to soft and hard keratinizing epithelial structures of the hair follicle and the filiform tongue papilla.At present, of the 54 human keratins, only five members, i.e. the type I keratins K23, K24, and the type II keratins K78, K79, and K80 (1-3), have been characterized essentially at the gene/cDNA level, whereas detailed studies on the expression of the respective mRNAs and their proteins in human epithelia are still missing. To close this gap, we set out to investigate the expression characteristics of the type II keratin K80 (previously designated Kb20 (4)). Earlier bioinformatic analyses have shown that the KRT80 gene is located at the centromeric end of the human type II keratin gene domain on chromosome 12q13.13 (Fig. 1A). The isolated K80 cDNA encodes a 452-amino acid protein with a calculated molecular mass of 50.5 kDa and an isoelectric point of 5.47 (2).Remarkably, ␣-helical rod domain-based evolutionary analyses of the 26 type II keratins revealed a conspicuously long branch length for K80, thus indicating a relatively low homology of its ␣-helix to those of the remaining type II epithelial keratins, whereas its sequence affinity to type II hair keratins was relatively high (Fig. 1B, and Ref. 2). This was also reflected in the non-␣-helical K80 end domains that contained a relatively high number of proline and cysteine residues along with the complete absence of GGG or GGX repeats (2), typically found in the head and tail domains of most type II epithelial keratins (Fig....

A primer for studying cell cycle dynamics of the human hair follicle

“…Moreover, while it is now understood that, regarding cell cycle activity, even telogen HFs are far less ‘quiescent’ than long assumed (at least in the mouse) , the cell cycle dynamics of human telogen HFs remain to be systematically characterized . Thus, our basic understanding of human HF cell cycle dynamics stands in stark contrast to our knowledge of the human HF's expression of differentiation‐associated proteins, most prominently HF‐associated keratins . The current Methods Review hopes to encourage other colleagues in the field to help close these important gaps in our understanding of human HF biology by applying the methods recommended below.…”

Evolution of the vertebrate beaded filament protein, Bfsp2; comparing the in vitro assembly properties of a “tailed” zebrafish Bfsp2 to its “tailless” human orthologue

“…Interestingly, phosphorylation of Bfsp2 is a mechanism to alter the subcellular distribution of beaded filaments (Ireland et al, 1993) and so Bfsp2 and beaded filaments as well as lens crystallins (Kappe et al, 2010) are potential candidates to elicit such a change in lens refractive power. Thus far, however, it is only zebrafish that have evidence of alternative splicing to further increase Bfsp2 diversity (see Table 1), but where this occurs in mammalian intermediate filament proteins it can change the assembly properties (Perng et al, 2008) and alter function (Langbein et al, 2010). …”

Few Simple Sequence Repeats in Human Hair

“…The differences in repeat conservation is despite close phylogenetic relationship of keratin Type II proteins KRT86, KRT81 and KRT83 proteins 8,85 . Further, disparity in repeats found in these genes is intriguing despite their expression in the same regions of hair and possibly dimerisation with similar Type I keratins 5,6 (Table-1a 2, 3, 6-9, 57-59 and b 2,3,8,[57][58][59] ). KRT39 and KRT40 show differences in repeat types and their conservation, where KRT39 has less diversity of repeat motifs compared with KRT40.…”

“…Despite same evolutionary branching, these two genes do not have >60% sequence similarity with each other and other members of Type I keratin; their expression patterns are different and form dimers with different Type II genes 5,6,8 (Table-1a 2, 3, 6-9, 57-59 and b 2,3,8,[57][58][59] ). It would be interesting to investigate whether the repeat differences in these genes have any contribution in either their evolutionary divergence, regulation of expression and or association with respective Type II keratins.…”

“…These differ from other keratins in having higher amount of sulphur in the head and tail domains 2,3 and cysteine residue compared with epithelial keratins [3][4][5][6] . In humans there are seventeen hair keratin genes encompassing eleven Type I keratins and six Type II keratins [5][6][7][8][9] . Though keratin genes of the same type are closely linked, Type I and Type II are present on human chromosome 17q12-21 and 12q13, respectively 1,2 .…”