Structural biology of hemidesmosomes

Hemidesmosomes are protein complexes that mediate the stable attachement of basal cells to the underlying basement membrane in epithelial tissues, such as the skin. They provide a link between the extracellular matrix and the intermediate filament cytoskeleton. Hemidesmosomes contain at least 5 components: the α6β4 integrin, plectin, the bullous pemphigoid antigens BPAG1e (also known as BP230) and BP180, and the tetraspanin CD151.

Integrin α6β4

Integrins are a family of hetero-dimeric transmembrane receptors that mediate cell adhesion and bi-directional signal transduction. The α6β4 integrin is a laminin receptor. The β4 subunit has an unusual cytoplasmic region, which is ~1000 residues long and contains four fibronectin type III (FnIII) domains and a Calxβ domain. In 1999 we determined the crystal structure of the first tandem pair of FnIII domains of β4, a region that it is essential for the binding of β4 to plectin and for the stability of hemidesmosomes. Point mutations within the second FnIII are linked to nonlethal forms of a skin blistering disorder termed epidermolysis bullosa.

Plectin

Plectin is a versatile cytoskeletal linker that belongs to the plakin protein family. In hemidesmosomes plectin provides a direct link between the integrin α6β4 and the cytokeratin system. Plectin is a large molecule (~500 kD) with a tripartite organization: it contains N- and C-terminal regions that harbor multiple protein-protein interaction sites and a central rod domain involved in oligomerization. We have focused our studies of plectin on the N-terminal region, which contains a binding site for the cytoplasmic domain of the β4 integrin.

We have solved the crystal structure of the actin binding domain (ABD) present in the N-terminal end of plectin. The ABD is built up of two calponin homology (CH) domains.

Adjacent to the ABD extends a region of about 1000 residues termed the plakin domain that is conserved among the plakin family. Recently we have elucidated the crystal structure of the N-terminal region of the plakin domain of plectin, which also contributes to the binding to the integrin β4. The structure is formed by two spectrin repeats, connected by a α-helical linker.