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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

Molecular organization of HDs and a model of the HD disassembly mechanism. a Schematically drawn are the six key components of type I HDs (integrin subunits α6 and β4, CD151, BPAG2, BPAG1e and plectin 1a), the extracellular basement membrane (BM) containing the ligand laminin-332 and the intracellular binding partner, intermediate filaments (IFs) of the keratin (K5/K14) type. The various protein domains involved in binding of integrin β4 to plectin 1a and in the linkage of the HD complex to keratin IFs are indicated. b Mechanism of growth factor-induced dissociation of the integrin β4–plectin 1a complex. For simplicity, only integrin α6β4, plectin 1a and K5/K14 IFs are shown. Growth factor-induced phosphorylation of serine residues in the C-terminal integrin β4 tail and CS domains results in the dissociation of integrin β4 from plectin 1a’s plakin and ABD domains. Subsequent interaction of plectin 1a’s ABD with the Ca++-bound form of calmodulin (CaM) prevents re-association of the integrin β4-plectin 1a complex. 1a, isoform-specific N-terminal domain preceding the ABD of plectin 1a; Calx-β, Na+–Ca2+ exchanger motif; CH1,2, calponin homology domains 1 and 2; CS, connecting segment; FnIII-1,-2,-3,-4, fibronectin type III domains 1–4; PRDs, plectin repeat domains
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Fig2: Molecular organization of HDs and a model of the HD disassembly mechanism. a Schematically drawn are the six key components of type I HDs (integrin subunits α6 and β4, CD151, BPAG2, BPAG1e and plectin 1a), the extracellular basement membrane (BM) containing the ligand laminin-332 and the intracellular binding partner, intermediate filaments (IFs) of the keratin (K5/K14) type. The various protein domains involved in binding of integrin β4 to plectin 1a and in the linkage of the HD complex to keratin IFs are indicated. b Mechanism of growth factor-induced dissociation of the integrin β4–plectin 1a complex. For simplicity, only integrin α6β4, plectin 1a and K5/K14 IFs are shown. Growth factor-induced phosphorylation of serine residues in the C-terminal integrin β4 tail and CS domains results in the dissociation of integrin β4 from plectin 1a’s plakin and ABD domains. Subsequent interaction of plectin 1a’s ABD with the Ca++-bound form of calmodulin (CaM) prevents re-association of the integrin β4-plectin 1a complex. 1a, isoform-specific N-terminal domain preceding the ABD of plectin 1a; Calx-β, Na+–Ca2+ exchanger motif; CH1,2, calponin homology domains 1 and 2; CS, connecting segment; FnIII-1,-2,-3,-4, fibronectin type III domains 1–4; PRDs, plectin repeat domains

Mentions: Integrin α6β4 is one of the two transmembrane components of HDs (Fig. 2a). It acts as a laminin-332 receptor. Like other members of the integrin family of extracellular matrix (ECM) receptors, integrin α6β4 is a non-covalent heterodimer formed by two type I (C terminus is intracellular) transmembrane subunits, α and β (Sonnenberg et al. 1991). The genes encoding the α6 and β4 subunits have been mapped to chromosomes 2q31.1 and 17q25.1, respectively (Hogervorst et al. 1991; Iacovacci et al. 1997). Integrin α6β4 is widely expressed in epithelia where it is found in HDs but it is also expressed in several non-epithelial cell types, including endothelial cells, astrocytes, neurons and Schwann cells (Wagner et al. 1997; Nodari et al. 2008; Su et al. 2008; Van der Zee et al. 2008; Welser-Alves et al. 2013). Integrin α6 is a conventional integrin α subunit, whereas integrin β4 has a unique cytoplasmic domain that is much larger (>1,000 residues) than that of other integrin β subunits and shares no similarity with them (Hogervorst et al. 1990; Tamura et al. 1990). The cytoplasmic domain of integrin β4 is composed of five globular domains: a membrane-proximal Na+–Ca2+ (Calx-β) exchanger motif and two pairs of fibronectin type III (FnIII) domains (FnIII-1,2 and FnIII-3,4); the two pairs of FnIII domains are separated by a region named the connecting segment (CS) and a C-terminal tail extends downstream of FnIII-4 (Hogervorst et al. 1990; Suzuki and Naitoh 1990). The cytoplasmic domain of integrin β4 mediates most of the intracellular interactions of the receptor, including those with the plakin family members P1a and BPAG1e, as well as with the transmembrane protein BPAG2 (Fig. 2a). Via binding to P1a and BPAG1e, integrin α6β4 associates with the keratin IF cytoskeleton rather than with actin filaments, making this integrin heterodimer unique among the other family members (Rezniczek et al. 1998; Fontao et al. 2001; Koster et al. 2004). The α6 subunit consists in a long N-terminal extracellular domain followed by the transmembrane domain and a short intracellular domain (Hogervorst et al. 1991). The extracellular domain of integrin α6 harbors binding sites for BP180, CD151 and laminin-322 (Hopkinson et al. 1995, 1998; Kazarov et al. 2002). The large cytoplasmic domain of integrin β4 also interacts with a number of signaling intermediates involved in the regulation of cell proliferation and survival (Margadant et al. 2010). However, whether integrin α6β4 is capable of signaling when it resides within the HD has not been clarified and it seems more likely that it plays such a role when not incorporated into the HD structure, such as during keratinocyte migration or carcinoma cell invasion (Wilhelmsen et al. 2006).Fig. 2


Molecular architecture and function of the hemidesmosome.

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

Molecular organization of HDs and a model of the HD disassembly mechanism. a Schematically drawn are the six key components of type I HDs (integrin subunits α6 and β4, CD151, BPAG2, BPAG1e and plectin 1a), the extracellular basement membrane (BM) containing the ligand laminin-332 and the intracellular binding partner, intermediate filaments (IFs) of the keratin (K5/K14) type. The various protein domains involved in binding of integrin β4 to plectin 1a and in the linkage of the HD complex to keratin IFs are indicated. b Mechanism of growth factor-induced dissociation of the integrin β4–plectin 1a complex. For simplicity, only integrin α6β4, plectin 1a and K5/K14 IFs are shown. Growth factor-induced phosphorylation of serine residues in the C-terminal integrin β4 tail and CS domains results in the dissociation of integrin β4 from plectin 1a’s plakin and ABD domains. Subsequent interaction of plectin 1a’s ABD with the Ca++-bound form of calmodulin (CaM) prevents re-association of the integrin β4-plectin 1a complex. 1a, isoform-specific N-terminal domain preceding the ABD of plectin 1a; Calx-β, Na+–Ca2+ exchanger motif; CH1,2, calponin homology domains 1 and 2; CS, connecting segment; FnIII-1,-2,-3,-4, fibronectin type III domains 1–4; PRDs, plectin repeat domains
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Related In: Results  -  Collection

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Fig2: Molecular organization of HDs and a model of the HD disassembly mechanism. a Schematically drawn are the six key components of type I HDs (integrin subunits α6 and β4, CD151, BPAG2, BPAG1e and plectin 1a), the extracellular basement membrane (BM) containing the ligand laminin-332 and the intracellular binding partner, intermediate filaments (IFs) of the keratin (K5/K14) type. The various protein domains involved in binding of integrin β4 to plectin 1a and in the linkage of the HD complex to keratin IFs are indicated. b Mechanism of growth factor-induced dissociation of the integrin β4–plectin 1a complex. For simplicity, only integrin α6β4, plectin 1a and K5/K14 IFs are shown. Growth factor-induced phosphorylation of serine residues in the C-terminal integrin β4 tail and CS domains results in the dissociation of integrin β4 from plectin 1a’s plakin and ABD domains. Subsequent interaction of plectin 1a’s ABD with the Ca++-bound form of calmodulin (CaM) prevents re-association of the integrin β4-plectin 1a complex. 1a, isoform-specific N-terminal domain preceding the ABD of plectin 1a; Calx-β, Na+–Ca2+ exchanger motif; CH1,2, calponin homology domains 1 and 2; CS, connecting segment; FnIII-1,-2,-3,-4, fibronectin type III domains 1–4; PRDs, plectin repeat domains
Mentions: Integrin α6β4 is one of the two transmembrane components of HDs (Fig. 2a). It acts as a laminin-332 receptor. Like other members of the integrin family of extracellular matrix (ECM) receptors, integrin α6β4 is a non-covalent heterodimer formed by two type I (C terminus is intracellular) transmembrane subunits, α and β (Sonnenberg et al. 1991). The genes encoding the α6 and β4 subunits have been mapped to chromosomes 2q31.1 and 17q25.1, respectively (Hogervorst et al. 1991; Iacovacci et al. 1997). Integrin α6β4 is widely expressed in epithelia where it is found in HDs but it is also expressed in several non-epithelial cell types, including endothelial cells, astrocytes, neurons and Schwann cells (Wagner et al. 1997; Nodari et al. 2008; Su et al. 2008; Van der Zee et al. 2008; Welser-Alves et al. 2013). Integrin α6 is a conventional integrin α subunit, whereas integrin β4 has a unique cytoplasmic domain that is much larger (>1,000 residues) than that of other integrin β subunits and shares no similarity with them (Hogervorst et al. 1990; Tamura et al. 1990). The cytoplasmic domain of integrin β4 is composed of five globular domains: a membrane-proximal Na+–Ca2+ (Calx-β) exchanger motif and two pairs of fibronectin type III (FnIII) domains (FnIII-1,2 and FnIII-3,4); the two pairs of FnIII domains are separated by a region named the connecting segment (CS) and a C-terminal tail extends downstream of FnIII-4 (Hogervorst et al. 1990; Suzuki and Naitoh 1990). The cytoplasmic domain of integrin β4 mediates most of the intracellular interactions of the receptor, including those with the plakin family members P1a and BPAG1e, as well as with the transmembrane protein BPAG2 (Fig. 2a). Via binding to P1a and BPAG1e, integrin α6β4 associates with the keratin IF cytoskeleton rather than with actin filaments, making this integrin heterodimer unique among the other family members (Rezniczek et al. 1998; Fontao et al. 2001; Koster et al. 2004). The α6 subunit consists in a long N-terminal extracellular domain followed by the transmembrane domain and a short intracellular domain (Hogervorst et al. 1991). The extracellular domain of integrin α6 harbors binding sites for BP180, CD151 and laminin-322 (Hopkinson et al. 1995, 1998; Kazarov et al. 2002). The large cytoplasmic domain of integrin β4 also interacts with a number of signaling intermediates involved in the regulation of cell proliferation and survival (Margadant et al. 2010). However, whether integrin α6β4 is capable of signaling when it resides within the HD has not been clarified and it seems more likely that it plays such a role when not incorporated into the HD structure, such as during keratinocyte migration or carcinoma cell invasion (Wilhelmsen et al. 2006).Fig. 2

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