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Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family.

Wu Z, Hansmann B, Meyer-Hoffert U, Gläser R, Schröder JM - PLoS ONE (2009)

Bottom Line: We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta.We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis.Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany.

ABSTRACT
Genes of the S100 fused-type protein (SFTP) family are clustered within the epidermal differentiation complex and encode essential components that maintain epithelial homeostasis and barrier functions. Recent genetic studies have shown that mutations within the gene encoding the SFTP filaggrin cause ichthyosis vulgaris and are major predisposing factors for atopic dermatitis. As a vital component of healthy skin, filaggrin is also a precursor of natural moisturizing factors. Here we present the discovery of a member of this family, designated as filaggrin-2 (FLG2) that is expressed in human skin. The FLG2 gene encodes a histidine- and glutamine-rich protein of approximately 248 kDa, which shares common structural features with other SFTP members, in particular filaggrin. We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta. In cultured primary keratinocytes, FLG2 mRNA expression displayed almost the same kinetics as that of filaggrin following Ca(2+) stimulation, suggesting an important role in molecular regulation of epidermal terminal differentiation. We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis. Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.

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Structural characteristics of the filaggrin-2 protein.(A) A schematic diagram of human filaggrin-2. The N-terminal S100 and EF-hand domains were detected with the SMART algorithm. Repeat domains (A1 to 9 and B1 to14) were first detected by the RADAR program and then refined manually. (B) Multiple sequence alignment of N-terminal S100 domains from all known SFTP proteins. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among SFTP members. The positions of the S100 and EF-hand regions are indicated above the alignment. FLG, filaggrin; FLG2, filaggrin-2; HRNR, hornerin; RPTN, repetin; TCHH, trichohyalin; CRNN, cornulin. (C–D) Multiple sequence alignment of A-type (C) and B-type repeats (D) of FLG2, respectively. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among repeat domains. Here, HRNR represents hornerin (GeneBank Accession No. GI:57864582) residues 1807–1884; FLG represents profilaggrin (GeneBank Accession No. GI:60097902) residues 3745–3821.
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pone-0005227-g002: Structural characteristics of the filaggrin-2 protein.(A) A schematic diagram of human filaggrin-2. The N-terminal S100 and EF-hand domains were detected with the SMART algorithm. Repeat domains (A1 to 9 and B1 to14) were first detected by the RADAR program and then refined manually. (B) Multiple sequence alignment of N-terminal S100 domains from all known SFTP proteins. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among SFTP members. The positions of the S100 and EF-hand regions are indicated above the alignment. FLG, filaggrin; FLG2, filaggrin-2; HRNR, hornerin; RPTN, repetin; TCHH, trichohyalin; CRNN, cornulin. (C–D) Multiple sequence alignment of A-type (C) and B-type repeats (D) of FLG2, respectively. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among repeat domains. Here, HRNR represents hornerin (GeneBank Accession No. GI:57864582) residues 1807–1884; FLG represents profilaggrin (GeneBank Accession No. GI:60097902) residues 3745–3821.

Mentions: The FLG2 gene contains an open reading frame of 7176 nucleotides, encoding a protein of 2391 amino acids. By using SMART to explore domain architectures, this deduced protein sequence harboured an S100/ICaBP type calcium binding domain (residues 4–46) [41] and an EF-hand domain (residues 53–81) at its amino terminus. Analysis of the repeat contents using the computer program RADAR, followed by manual adjustment, revealed that this protein contains a large central repetitive region consisting of two types of multiple tandem repeats (Fig. 2A). Amino acid sequence comparison of all currently known human SFTPs, including profilaggrin, trichohyalin, repetin, cornulin, hornerin and filaggrin-2, indicated that they are highly conservative in inferring homology of the N-terminal 81-residue region containing the S100 and EF-hand domains (Fig. 2B).


Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family.

Wu Z, Hansmann B, Meyer-Hoffert U, Gläser R, Schröder JM - PLoS ONE (2009)

Structural characteristics of the filaggrin-2 protein.(A) A schematic diagram of human filaggrin-2. The N-terminal S100 and EF-hand domains were detected with the SMART algorithm. Repeat domains (A1 to 9 and B1 to14) were first detected by the RADAR program and then refined manually. (B) Multiple sequence alignment of N-terminal S100 domains from all known SFTP proteins. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among SFTP members. The positions of the S100 and EF-hand regions are indicated above the alignment. FLG, filaggrin; FLG2, filaggrin-2; HRNR, hornerin; RPTN, repetin; TCHH, trichohyalin; CRNN, cornulin. (C–D) Multiple sequence alignment of A-type (C) and B-type repeats (D) of FLG2, respectively. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among repeat domains. Here, HRNR represents hornerin (GeneBank Accession No. GI:57864582) residues 1807–1884; FLG represents profilaggrin (GeneBank Accession No. GI:60097902) residues 3745–3821.
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Related In: Results  -  Collection

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pone-0005227-g002: Structural characteristics of the filaggrin-2 protein.(A) A schematic diagram of human filaggrin-2. The N-terminal S100 and EF-hand domains were detected with the SMART algorithm. Repeat domains (A1 to 9 and B1 to14) were first detected by the RADAR program and then refined manually. (B) Multiple sequence alignment of N-terminal S100 domains from all known SFTP proteins. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among SFTP members. The positions of the S100 and EF-hand regions are indicated above the alignment. FLG, filaggrin; FLG2, filaggrin-2; HRNR, hornerin; RPTN, repetin; TCHH, trichohyalin; CRNN, cornulin. (C–D) Multiple sequence alignment of A-type (C) and B-type repeats (D) of FLG2, respectively. The alignment was generated by using M-COFFEE and displayed by using GeneDoc. Identical residues are boxed in black while gray boxes mark partially conserved residues. The darker the shading, the more the amino acids are conserved among repeat domains. Here, HRNR represents hornerin (GeneBank Accession No. GI:57864582) residues 1807–1884; FLG represents profilaggrin (GeneBank Accession No. GI:60097902) residues 3745–3821.
Mentions: The FLG2 gene contains an open reading frame of 7176 nucleotides, encoding a protein of 2391 amino acids. By using SMART to explore domain architectures, this deduced protein sequence harboured an S100/ICaBP type calcium binding domain (residues 4–46) [41] and an EF-hand domain (residues 53–81) at its amino terminus. Analysis of the repeat contents using the computer program RADAR, followed by manual adjustment, revealed that this protein contains a large central repetitive region consisting of two types of multiple tandem repeats (Fig. 2A). Amino acid sequence comparison of all currently known human SFTPs, including profilaggrin, trichohyalin, repetin, cornulin, hornerin and filaggrin-2, indicated that they are highly conservative in inferring homology of the N-terminal 81-residue region containing the S100 and EF-hand domains (Fig. 2B).

Bottom Line: We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta.We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis.Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany.

ABSTRACT
Genes of the S100 fused-type protein (SFTP) family are clustered within the epidermal differentiation complex and encode essential components that maintain epithelial homeostasis and barrier functions. Recent genetic studies have shown that mutations within the gene encoding the SFTP filaggrin cause ichthyosis vulgaris and are major predisposing factors for atopic dermatitis. As a vital component of healthy skin, filaggrin is also a precursor of natural moisturizing factors. Here we present the discovery of a member of this family, designated as filaggrin-2 (FLG2) that is expressed in human skin. The FLG2 gene encodes a histidine- and glutamine-rich protein of approximately 248 kDa, which shares common structural features with other SFTP members, in particular filaggrin. We found that FLG2 transcripts are present in skin, thymus, tonsils, stomach, testis and placenta. In cultured primary keratinocytes, FLG2 mRNA expression displayed almost the same kinetics as that of filaggrin following Ca(2+) stimulation, suggesting an important role in molecular regulation of epidermal terminal differentiation. We provide evidences that like filaggrin, FLG2 is initially expressed by upper granular cells, proteolytically processed and deposited in the stratum granulosum and stratum corneum (SC) layers of normal epidermis. Thus, FLG2 and filaggrin may have overlapping and perhaps synergistic roles in the formation of the epidermal barrier, protecting the skin from environmental insults and the escape of moisture by offering precursors of natural moisturizing factors.

Show MeSH
Related in: MedlinePlus