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.
Highlights
Hemidesmosomes (HDs) are highly specialized integrinmediated epithelial attachment structures that make cells firmly adhere to the extracellular matrix by establishing a link between the underlying basement membrane (BM) and the internal mechanical stress-resilient keratin intermediate filament (IF) network
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
The crystal structures of plectin’s actin-binding domain (ABD) as well as that of the primary plectin–integrin β4 complex have been resolved (Garcia-Alvarez et al 2003; Sevcik et al 2004; de Pereda et al 2009a). These analyses showed that the ABD of plectin consists in two calponin homology (CH) domains arranged in a closed conformation and that plectin binds to integrin β4 through its CH1 domain, whereas integrin β4 binds to plectin through its FNIII-2 domain
Summary
Hemidesmosomes (HDs) are highly specialized integrinmediated epithelial attachment structures that make cells firmly adhere to the extracellular matrix by establishing a link between the underlying basement membrane (BM) and the internal mechanical stress-resilient keratin intermediate filament (IF) network. 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). We will focus on what is known about the mechanisms of assembly, stabilization and turnover of HDs, with special attention attributed to post-translational and transcriptional regulation
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