Ultrastructural Localization of S100A3, a Cysteine-rich, Calcium Binding Protein, in Human Scalp Hair Shafts Revealed by Rapid-freezing Immunocytochemistry

Takami, Takeshi; Tajima, Toshihiro; Arai, Seiichi; Kizawa, Kenji; Uchiwa, Hideyo; Sasaki, Ichiro; Inoue, Takafumi

doi:10.1177/002215549904700411

Cited by 37 publications

(37 citation statements)

References 19 publications

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“…The mouse S100a3 gene was specifically expressed in dorsal skin containing hair follicles. Previous studies suggest a close association between S100a3 and epithelial differentiation leading to hair shaft formation (Takizawa et al, 1999;Ito and Kizawa, 2001). In this study, we found that the S100A3 protein appeared in the sebaceous glands at telogen and the cuticles of the hair shafts at anagen (Figure 2).…”

Section: Discussionsupporting

confidence: 67%

“…It is unique among the S100 proteins in that it has the highest cysteine content (10%) (Kizawa et al, 2013). It is specifically expressed in cuticular cells, and to a lesser extent in the cortical cells of hair follicles in humans (Kizawa et al, 1996;Takizawa et al, 1999), mice (Kizawa et al, 1998), and rats (Kizawa and Ito, 2005). In addition, S100A3 is expressed in head and neck cancer (Tyszkiewicz et al, 2014), breast cancer (Lloyd et al, 1996), gastric cancer (Liu et al, 2008), colorectal cancer (Liu et al, 2013), bladder cancer (Yao et al, 2007), and astrocytic tumors (Camby et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Blockade of S100A3 activity inhibits murine hair growth

Guan¹,

Deng²,

Yu³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Using mouse gene expression microarray analysis, we obtained dynamic expression profiles of the whole genome in a depilationinduced hair growth mouse model. S100A3 expression increased during the anagen phase and returned to normal during the telogen phase. The effects of S100A3 blockade on the hair growth cycle were examined in mice after subcutaneous injection of an anti-mouse S100A3 antibody. Protein localization of S100A3 was confined to the hair shafts during the anagen phase and the sebaceous glands during the telogen phase. S100A3 blockade delayed hair follicle entry into the anagen phase, decreased hair elongation, and reduced the number of hair follicles in the subcutis, which correlated with the downregulated expression of hair growth inductionrelated genes in vivo. The present study demonstrates that anti-S100A3 antibody inhibits mouse hair growth, suggesting that S100A3 can be used as a target for hair loss treatment.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Blockade of S100A3 activity inhibits murine hair growth

Guan¹,

Deng²,

Yu³

et al. 2015

Genet. Mol. Res.

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“…The latter hypothesis could be confirmed by immunohistochemical analyses which demonstrated that S100A5 is only expressed in a few distinct brain areas, namely the olfactory bulb, the brainstem, and the spinal trigeminal tract. This expression pattern is somewhat reminiscent of that of S100A3 (36,37) and clearly distinct from other S100 proteins such as S100A6 and S100B. S100A5 displays high affinity for Ca 2ϩ when compared with other S100 proteins analyzed under identical experimental conditions with the same methodology (Table II).…”

Section: Discussionmentioning

confidence: 72%

Brain S100A5 Is a Novel Calcium-, Zinc-, and Copper Ion-binding Protein of the EF-hand Superfamily

Schäfer

Fritschy

Murmann

et al. 2000

Journal of Biological Chemistry

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S100A5 is a novel member of the EF-hand superfamily of calcium-binding proteins that is poorly characterized at the protein level. Immunohistochemical analysis demonstrates that it is expressed in very restricted regions of the adult brain. Here we characterized the human recombinant S100A5, especially its interaction with Ca 2؉ , Zn 2؉ , and Cu 2؉. Flow dialysis revealed that the homodimeric S100A5 binds four Ca 2؉ ions with strong positive cooperativity and an affinity 20 -100-fold higher than the other S100 proteins studied under identical conditions. S100A5 also binds two Zn 2؉ ions and four Cu 2؉ ions per dimer. Cu 2؉ binding strongly impairs the binding of Ca 2؉ ; however, none of these ions change the ␣-helical-rich secondary structure. After covalent labeling of an exposed thiol with 2-(4-(iodoacetamide)anilino)-naphthalene-6-sulfonic acid, binding of Cu 2؉ , but not of Ca 2؉ or Zn 2؉ , strongly decreased its fluorescence. In light of the three-dimensional structure of S100 proteins, our data suggest that in each subunit the single Zn 2؉ site is located at the opposite side of the EF-hands. The two Cu 2؉ -binding sites likely share ligands of the EF-hands. The potential role of S100A5 in copper homeostasis is discussed.Calcium, a versatile second messenger of extracellular signals inside the cell, binds to a multitude of cytosolic Ca 2ϩ -binding proteins each of which can, in turn, regulate several effector proteins. The S100 protein family (18 different members) constitutes the largest group of Ca 2ϩ -binding proteins of the EF-hand type (1, 2). At least 13 S100 genes are clustered on human chromosome 1q21, leading to the designation S100A1 to S100A13 for the protein products of these genes (3). Their expression is cell-and tissue-specific, and different human diseases have been associated with deregulated expression (4, 5). S100 proteins are non-covalent homodimers with the notable exception of the heterodimeric S100A8-S100A9. Each monomer possesses 2 EF-hands as follows: a classical C-terminal EFhand with a canonical Ca 2ϩ -binding loop of 12 amino acids and a N-terminal EF-hand with a loop of 14 amino acids which is specific for S100 proteins. This structural difference likely is the reason for the large difference in the Ca 2ϩ affinities of the N-and C-terminal EF-hands. The affinities of S100 proteins for Ca 2ϩ are in general rather low with [Ca 2ϩ ] 0.5 1 values of 100 -300 mM (for review see Refs. 2 and 6), and in 6 out of 8 studied cases binding of Ca 2ϩ displays positive cooperativity. Zn 2ϩ binds to several S100 proteins; the Zn 2ϩ and Ca 2ϩ sites are distinct and can modify the affinity for Ca 2ϩ . S100B binds four Zn 2ϩ ions with concomitant 10-fold increases of the Ca 2ϩ affinity (7). High affinity binding of two Zn 2ϩ to the S100A12 dimer leads to induction of two high affinity Ca 2ϩ -binding sites (8). S100A3 binds eight Zn 2ϩ , but without effect on the affinity for Ca 2ϩ (9, 10). S100A2 binds four Zn 2ϩ with high affinity, in a manner antagonistic to Ca 2ϩ (11). Recently it was reported...

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“…In contrast, citrullinated S100A3 dimer assembled into a homotetramer. This irreversible modification of S100A3 appears to be a crucial step prior to its organization into the amorphous composites of the mature cuticles (25).…”

Section: Discussionmentioning

confidence: 99%

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

Kizawa¹,

Takahara

Troxler

et al. 2008

Journal of Biological Chemistry

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S100A3 is a unique member of the Ca 2؉ -binding S100 protein family with the highest cysteine content and affinity for Zn 2؉ . This protein is highly expressed in the differentiating cuticular cells within the hair follicle and organized into mature hair cuticles. Previous studies suggest a close association of S100A3 with epithelial differentiation, leading to hair shaft formation, but its molecular function is still unknown. By two-dimensional PAGE-Western blot analyses using a modified citrulline antibody, we discovered that more than half of the arginine residues of native S100A3 are progressively converted to citrullines by Ca 2؉ -dependent peptidylarginine deiminases. Confocal immunofluorescent microscopy showed that the cytoplasmic S100A3 within the cuticular layer is mostly co-localized with the type III isoform of peptidylarginine deiminase (PAD3) but not with PAD1. Recombinant PAD1 and PAD2 are capable of converting all 4 arginines in recombinant S100A3, whereas PAD3 specifically converts only Arg-51 into citrulline. Gel filtration analyses showed that either enzymatic conversion of Arg-51 in S100A3 to citrulline or its mutational substitution with alanine (R51A) promotes a homotetramer assembly. Fluorescent titration of R51A suggested that its potential Ca 2؉ binding property increased during tetramerization. A prototype structural model of the globular Ca 2؉ -bound S100A3 tetramer with citrulline residues is presented. High concentrations of S100A3 homotetramer might provide the millimolar level of Ca 2؉ required for hair cuticular barrier formation.

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Ultrastructural Localization of S100A3, a Cysteine-rich, Calcium Binding Protein, in Human Scalp Hair Shafts Revealed by Rapid-freezing Immunocytochemistry

Cited by 37 publications

References 19 publications

Blockade of S100A3 activity inhibits murine hair growth

Blockade of S100A3 activity inhibits murine hair growth

Brain S100A5 Is a Novel Calcium-, Zinc-, and Copper Ion-binding Protein of the EF-hand Superfamily

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

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