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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

Hypothetical model of HD stabilization through plectin self-association. a Three consecutive stages (i–iii) of inner plaque formation are depicted; for simplicity, only integrin α6β4 and plectin 1a molecules are shown. In a first step (i) a parallel plectin 1a dimer binds, via its N-terminal β4-binding domains (green), to the cytoplasmic tail (red) of plasma membrane (violet)-embedded integrin β4; plectin’s C-terminal domain (orange) makes the connection to keratin filaments. In a second step (ii), two plectin 1a dimers form a tetramer by lateral association of their central rod domains in an anti-parallel fashion, creating integrin β4 and K5/K14 binding sites at both ends of the tetramer. Further self-association of plectin rod segments leads to oligomeric sheet-like structures (iii). Note that self-association of plectin 1a molecules could lead to the clustering of integrin α6β4 (as depicted), or vice versa, clustered integrins may facilitate the focal recruitment of plectin molecules promoting their alignment and lateral association; also, targeting of plectin 1a molecules to integrin β4-could occur in their keratin IF-bound (as indicated) or unbound state. Opposing black arrows, plaque-stabilizing force component provided by laterally associated rod segments. b Structural model of an inner plaque assembled by the staggered lateral association of plectin dimers. Note the focal density of potential K5/K14 and integrin β4 binding sites on opposite sides of the plate structure. This model is based on the ultrastructural analysis of paracrystalline structures formed from recombinant full-length versions of plectin’s rod domain and the lateral association potential of intact plectin molecules isolated from cells (Walko et al. 2011)
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Fig3: Hypothetical model of HD stabilization through plectin self-association. a Three consecutive stages (i–iii) of inner plaque formation are depicted; for simplicity, only integrin α6β4 and plectin 1a molecules are shown. In a first step (i) a parallel plectin 1a dimer binds, via its N-terminal β4-binding domains (green), to the cytoplasmic tail (red) of plasma membrane (violet)-embedded integrin β4; plectin’s C-terminal domain (orange) makes the connection to keratin filaments. In a second step (ii), two plectin 1a dimers form a tetramer by lateral association of their central rod domains in an anti-parallel fashion, creating integrin β4 and K5/K14 binding sites at both ends of the tetramer. Further self-association of plectin rod segments leads to oligomeric sheet-like structures (iii). Note that self-association of plectin 1a molecules could lead to the clustering of integrin α6β4 (as depicted), or vice versa, clustered integrins may facilitate the focal recruitment of plectin molecules promoting their alignment and lateral association; also, targeting of plectin 1a molecules to integrin β4-could occur in their keratin IF-bound (as indicated) or unbound state. Opposing black arrows, plaque-stabilizing force component provided by laterally associated rod segments. b Structural model of an inner plaque assembled by the staggered lateral association of plectin dimers. Note the focal density of potential K5/K14 and integrin β4 binding sites on opposite sides of the plate structure. This model is based on the ultrastructural analysis of paracrystalline structures formed from recombinant full-length versions of plectin’s rod domain and the lateral association potential of intact plectin molecules isolated from cells (Walko et al. 2011)

Mentions: Beyond shedding light on the pathomechanism, studies on the Ogna mutation revealed a previously unknown feature of plectin molecules that potentially has great impact on HD structure and stability. It was reported that the central α-helical rod domains of coiled-coil plectin dimers can further associate laterally into extraordinary stable (paracrystalline) polymers. Based on these findings focal self-association of plectin molecules was proposed as a mechanism contributing to HD stabilization. According to the proposed model (Fig. 3), the recruitment of P1a to laminin-clustered integrin α6β4 molecules in developing HDs could lead to the proximal alignment of plectin’s rod domains, favoring their interaction and the assembly of compact highly ordered polymeric plectin structures. Thus, integrin α6β4-induced oligomerization of dimeric plectin molecules by lateral association of their RDs within the inner plaque structure would literally add another dimension (horizontal) to plectin’s HD-stabilizing potential. In this scenario, sufficient numbers of stable keratin-IF-linked HDs would only form if enough intact full-length P1a molecules are available for oligomerization. Whether other cytolinker proteins, such as the HD component BPAG1e, are also capable of lateral self-association and whether plectin can form hetero-oligomers with such proteins remains to be shown. Hetero-oligomer formation has previously been reported for plakins such as periplakin and envoplakin (Kalinin et al. 2004) and preliminary experiments using recombinant rod domains of plectin and BPAG1e indicate heterodimerization (authors’ unpublished results). Interestingly, a potential for self-interaction was also reported for integrin β4’s cytoplasmic domains (Rezniczek et al. 1998), a feature that may promote the clustering and alignment of integrins, providing a force component for HD stabilization similar to that of laterally-associated plectin rods.Fig. 3


Molecular architecture and function of the hemidesmosome.

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

Hypothetical model of HD stabilization through plectin self-association. a Three consecutive stages (i–iii) of inner plaque formation are depicted; for simplicity, only integrin α6β4 and plectin 1a molecules are shown. In a first step (i) a parallel plectin 1a dimer binds, via its N-terminal β4-binding domains (green), to the cytoplasmic tail (red) of plasma membrane (violet)-embedded integrin β4; plectin’s C-terminal domain (orange) makes the connection to keratin filaments. In a second step (ii), two plectin 1a dimers form a tetramer by lateral association of their central rod domains in an anti-parallel fashion, creating integrin β4 and K5/K14 binding sites at both ends of the tetramer. Further self-association of plectin rod segments leads to oligomeric sheet-like structures (iii). Note that self-association of plectin 1a molecules could lead to the clustering of integrin α6β4 (as depicted), or vice versa, clustered integrins may facilitate the focal recruitment of plectin molecules promoting their alignment and lateral association; also, targeting of plectin 1a molecules to integrin β4-could occur in their keratin IF-bound (as indicated) or unbound state. Opposing black arrows, plaque-stabilizing force component provided by laterally associated rod segments. b Structural model of an inner plaque assembled by the staggered lateral association of plectin dimers. Note the focal density of potential K5/K14 and integrin β4 binding sites on opposite sides of the plate structure. This model is based on the ultrastructural analysis of paracrystalline structures formed from recombinant full-length versions of plectin’s rod domain and the lateral association potential of intact plectin molecules isolated from cells (Walko et al. 2011)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Hypothetical model of HD stabilization through plectin self-association. a Three consecutive stages (i–iii) of inner plaque formation are depicted; for simplicity, only integrin α6β4 and plectin 1a molecules are shown. In a first step (i) a parallel plectin 1a dimer binds, via its N-terminal β4-binding domains (green), to the cytoplasmic tail (red) of plasma membrane (violet)-embedded integrin β4; plectin’s C-terminal domain (orange) makes the connection to keratin filaments. In a second step (ii), two plectin 1a dimers form a tetramer by lateral association of their central rod domains in an anti-parallel fashion, creating integrin β4 and K5/K14 binding sites at both ends of the tetramer. Further self-association of plectin rod segments leads to oligomeric sheet-like structures (iii). Note that self-association of plectin 1a molecules could lead to the clustering of integrin α6β4 (as depicted), or vice versa, clustered integrins may facilitate the focal recruitment of plectin molecules promoting their alignment and lateral association; also, targeting of plectin 1a molecules to integrin β4-could occur in their keratin IF-bound (as indicated) or unbound state. Opposing black arrows, plaque-stabilizing force component provided by laterally associated rod segments. b Structural model of an inner plaque assembled by the staggered lateral association of plectin dimers. Note the focal density of potential K5/K14 and integrin β4 binding sites on opposite sides of the plate structure. This model is based on the ultrastructural analysis of paracrystalline structures formed from recombinant full-length versions of plectin’s rod domain and the lateral association potential of intact plectin molecules isolated from cells (Walko et al. 2011)
Mentions: Beyond shedding light on the pathomechanism, studies on the Ogna mutation revealed a previously unknown feature of plectin molecules that potentially has great impact on HD structure and stability. It was reported that the central α-helical rod domains of coiled-coil plectin dimers can further associate laterally into extraordinary stable (paracrystalline) polymers. Based on these findings focal self-association of plectin molecules was proposed as a mechanism contributing to HD stabilization. According to the proposed model (Fig. 3), the recruitment of P1a to laminin-clustered integrin α6β4 molecules in developing HDs could lead to the proximal alignment of plectin’s rod domains, favoring their interaction and the assembly of compact highly ordered polymeric plectin structures. Thus, integrin α6β4-induced oligomerization of dimeric plectin molecules by lateral association of their RDs within the inner plaque structure would literally add another dimension (horizontal) to plectin’s HD-stabilizing potential. In this scenario, sufficient numbers of stable keratin-IF-linked HDs would only form if enough intact full-length P1a molecules are available for oligomerization. Whether other cytolinker proteins, such as the HD component BPAG1e, are also capable of lateral self-association and whether plectin can form hetero-oligomers with such proteins remains to be shown. Hetero-oligomer formation has previously been reported for plakins such as periplakin and envoplakin (Kalinin et al. 2004) and preliminary experiments using recombinant rod domains of plectin and BPAG1e indicate heterodimerization (authors’ unpublished results). Interestingly, a potential for self-interaction was also reported for integrin β4’s cytoplasmic domains (Rezniczek et al. 1998), a feature that may promote the clustering and alignment of integrins, providing a force component for HD stabilization similar to that of laterally-associated plectin rods.Fig. 3

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