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Molecular architecture and function of the hemidesmosome.

Walko G, Castañón MJ, Wiche G - Cell Tissue Res. (2014)

Bottom Line: The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes.Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering.Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London School of Medicine, 28th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

ABSTRACT
Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin α6β4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of a hemidesmosome and location of blisters within the skin in different types of EB. Keratin IFs are attached to the inner plaque of the hemidesmosome (HD). The outer plaque is parallel to the inner plaque, is slightly larger and lies on the plasma membrane of basal keratinocytes. Adjacent to the membrane are an electron-clear zone, the lamina lucida and an electron-dense zone, the lamina densa, which together make up the basal lamina (BL). Within the lamina lucida and directly below the plasma membrane, there is a thin electron dense line corresponding to the sub-basal dense plate. Fine anchoring filaments originate at HDs, traverse the lamina lucida and insert into the lamina densa. From the lamina densa collagenous anchoring fibrils extend into the dermal tissue. Outer brackets on the right indicate blister formation at different levels within the skin as is characteristic for the three major types of EB: EBS, within the epidermis; JEB, at the dermal-epidermal junction within the lamina lucida; DEB, in the upper layers of the dermis
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Fig1: Schematic representation of a hemidesmosome and location of blisters within the skin in different types of EB. Keratin IFs are attached to the inner plaque of the hemidesmosome (HD). The outer plaque is parallel to the inner plaque, is slightly larger and lies on the plasma membrane of basal keratinocytes. Adjacent to the membrane are an electron-clear zone, the lamina lucida and an electron-dense zone, the lamina densa, which together make up the basal lamina (BL). Within the lamina lucida and directly below the plasma membrane, there is a thin electron dense line corresponding to the sub-basal dense plate. Fine anchoring filaments originate at HDs, traverse the lamina lucida and insert into the lamina densa. From the lamina densa collagenous anchoring fibrils extend into the dermal tissue. Outer brackets on the right indicate blister formation at different levels within the skin as is characteristic for the three major types of EB: EBS, within the epidermis; JEB, at the dermal-epidermal junction within the lamina lucida; DEB, in the upper layers of the dermis

Mentions: Stable attachment of basal epidermal keratinocytes to the BM through HDs is of fundamental importance for maintaining skin integrity and epidermal homeostasis. Inherited or acquired diseases in which any of the HD components are affected lead to a variety of skin blistering disorders, collectively known as epidermolysis bullosa (EB) and characterized by tissue separation with blister formation within different layers of the skin. Based on where the tissue separation occurs, EB has been divided into three main categories: EB simplex (EBS), junctional EB (JEB) and dystrophic EB (DEB). In EBS, tissue separation occurs within the epidermis, in JEB, within the lamina lucida (between the dermis and epidermis) and in DEB, in the papillary dermis at the level of the anchoring fibrils (Fig. 1) (Jonkman 1999; Bruckner-Tuderman 2010; Fine et al. 2014). Mutations in at least 12 distinct genes encoding structural components of HDs have been identified as a causative of these different types of EB (Fine et al. 2014). Common clinical features include extreme skin fragility and the development of blisters and erosions in response to slight mechanical trauma. Additional extracutaneous complications associated with different variants of EB include corneal erosions, tracheal erosion and gastrointestinal blisters, dental abnormalities, nail dystrophy, esophageal strictures, pyloric atresia, muscular dystrophy and musculoskeletal deformities especially in the mittens (Pulkkinen and Uitto 1999; Fine and Mellerio 2009a, b). EBS is the most common type of EB, ranging in severity from very severe to relatively mild; most cases are caused by dominant mutations in the keratin genes KRT5 or KRT14, followed by recessive mutations in the genes coding for plectin (PLEC) and BPAG1e (DYS). JEB is caused by mutations in the integrin α6 (ITGA6), integrin β4 (ITGB4), BPAG2 (COL17A1) and laminin 322 (LAMA3, LAMB3, LAMC2) genes; JEB is a severe blistering disease with recessive inheritance. DEB is caused by mutations in the collagen VII gene (COL7A1); the recessive inherited form is the most severe type of EB. While intact HDs are required to connect the epidermis to the underlying dermis, remodeling and dissolution of HDs are important for a variety of biological processes, such as during terminal differentiation when basal keratinocytes detach from the BM to allow for their migration toward the suprabasal epidermal layers and for migration of keratinocytes during wound healing and carcinoma invasion of skin. In these processes, cells disassemble their HDs in order to loosen their tight attachment to the basement membrane and become migratory (Wilhelmsen et al. 2006; Margadant et al. 2010; Hopkinson et al. 2014). In contrast to skin, keratinocytes and other epithelial cells in culture fail to assemble bona fide HDs. Rather, HD-enriched protein complexes (HPCs), which have also been termed stable anchoring complexes (SACs), are found along the substrate-attached basal surface of such cells (Carter et al. 1990; Ozawa et al. 2010). HPCs are not static, exhibiting dynamic properties during cell migration (Geuijen and Sonnenberg 2002; Tsuruta et al. 2003; Ozawa et al. 2010).Fig. 1


Molecular architecture and function of the hemidesmosome.

Walko G, Castañón MJ, Wiche G - Cell Tissue Res. (2014)

Schematic representation of a hemidesmosome and location of blisters within the skin in different types of EB. Keratin IFs are attached to the inner plaque of the hemidesmosome (HD). The outer plaque is parallel to the inner plaque, is slightly larger and lies on the plasma membrane of basal keratinocytes. Adjacent to the membrane are an electron-clear zone, the lamina lucida and an electron-dense zone, the lamina densa, which together make up the basal lamina (BL). Within the lamina lucida and directly below the plasma membrane, there is a thin electron dense line corresponding to the sub-basal dense plate. Fine anchoring filaments originate at HDs, traverse the lamina lucida and insert into the lamina densa. From the lamina densa collagenous anchoring fibrils extend into the dermal tissue. Outer brackets on the right indicate blister formation at different levels within the skin as is characteristic for the three major types of EB: EBS, within the epidermis; JEB, at the dermal-epidermal junction within the lamina lucida; DEB, in the upper layers of the dermis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4544487&req=5

Fig1: Schematic representation of a hemidesmosome and location of blisters within the skin in different types of EB. Keratin IFs are attached to the inner plaque of the hemidesmosome (HD). The outer plaque is parallel to the inner plaque, is slightly larger and lies on the plasma membrane of basal keratinocytes. Adjacent to the membrane are an electron-clear zone, the lamina lucida and an electron-dense zone, the lamina densa, which together make up the basal lamina (BL). Within the lamina lucida and directly below the plasma membrane, there is a thin electron dense line corresponding to the sub-basal dense plate. Fine anchoring filaments originate at HDs, traverse the lamina lucida and insert into the lamina densa. From the lamina densa collagenous anchoring fibrils extend into the dermal tissue. Outer brackets on the right indicate blister formation at different levels within the skin as is characteristic for the three major types of EB: EBS, within the epidermis; JEB, at the dermal-epidermal junction within the lamina lucida; DEB, in the upper layers of the dermis
Mentions: Stable attachment of basal epidermal keratinocytes to the BM through HDs is of fundamental importance for maintaining skin integrity and epidermal homeostasis. Inherited or acquired diseases in which any of the HD components are affected lead to a variety of skin blistering disorders, collectively known as epidermolysis bullosa (EB) and characterized by tissue separation with blister formation within different layers of the skin. Based on where the tissue separation occurs, EB has been divided into three main categories: EB simplex (EBS), junctional EB (JEB) and dystrophic EB (DEB). In EBS, tissue separation occurs within the epidermis, in JEB, within the lamina lucida (between the dermis and epidermis) and in DEB, in the papillary dermis at the level of the anchoring fibrils (Fig. 1) (Jonkman 1999; Bruckner-Tuderman 2010; Fine et al. 2014). Mutations in at least 12 distinct genes encoding structural components of HDs have been identified as a causative of these different types of EB (Fine et al. 2014). Common clinical features include extreme skin fragility and the development of blisters and erosions in response to slight mechanical trauma. Additional extracutaneous complications associated with different variants of EB include corneal erosions, tracheal erosion and gastrointestinal blisters, dental abnormalities, nail dystrophy, esophageal strictures, pyloric atresia, muscular dystrophy and musculoskeletal deformities especially in the mittens (Pulkkinen and Uitto 1999; Fine and Mellerio 2009a, b). EBS is the most common type of EB, ranging in severity from very severe to relatively mild; most cases are caused by dominant mutations in the keratin genes KRT5 or KRT14, followed by recessive mutations in the genes coding for plectin (PLEC) and BPAG1e (DYS). JEB is caused by mutations in the integrin α6 (ITGA6), integrin β4 (ITGB4), BPAG2 (COL17A1) and laminin 322 (LAMA3, LAMB3, LAMC2) genes; JEB is a severe blistering disease with recessive inheritance. DEB is caused by mutations in the collagen VII gene (COL7A1); the recessive inherited form is the most severe type of EB. While intact HDs are required to connect the epidermis to the underlying dermis, remodeling and dissolution of HDs are important for a variety of biological processes, such as during terminal differentiation when basal keratinocytes detach from the BM to allow for their migration toward the suprabasal epidermal layers and for migration of keratinocytes during wound healing and carcinoma invasion of skin. In these processes, cells disassemble their HDs in order to loosen their tight attachment to the basement membrane and become migratory (Wilhelmsen et al. 2006; Margadant et al. 2010; Hopkinson et al. 2014). In contrast to skin, keratinocytes and other epithelial cells in culture fail to assemble bona fide HDs. Rather, HD-enriched protein complexes (HPCs), which have also been termed stable anchoring complexes (SACs), are found along the substrate-attached basal surface of such cells (Carter et al. 1990; Ozawa et al. 2010). HPCs are not static, exhibiting dynamic properties during cell migration (Geuijen and Sonnenberg 2002; Tsuruta et al. 2003; Ozawa et al. 2010).Fig. 1

Bottom Line: The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes.Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering.Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London School of Medicine, 28th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

ABSTRACT
Hemidesmosomes are multiprotein complexes that facilitate the stable adhesion of basal epithelial cells to the underlying basement membrane. The mechanical stability of hemidesmosomes relies on multiple interactions of a few protein components that form a membrane-embedded tightly-ordered complex. The core of this complex is provided by integrin α6β4 and P1a, an isoform of the cytoskeletal linker protein plectin that is specifically associated with hemidesmosomes. Integrin α6β4 binds to the extracellular matrix protein laminin-332, whereas P1a forms a bridge to the cytoplasmic keratin intermediate filament network. Other important components are BPAG1e, the epithelial isoform of bullous pemphigoid antigen 1, BPAG2, a collagen-type transmembrane protein and CD151. Inherited or acquired diseases in which essential components of the hemidesmosome are missing or structurally altered result in tissue fragility and blistering. Modulation of hemidesmosome function is of crucial importance for a variety of biological processes, such as terminal differentiation of basal keratinocytes and keratinocyte migration during wound healing and carcinoma invasion. Here, we review the molecular characteristics of the proteins that make up the hemidesmosome core structure and summarize the current knowledge about how their assembly and turnover are regulated by transcriptional and post-translational mechanisms.

No MeSH data available.


Related in: MedlinePlus