title: Two different mutations in the cytoplasmic domain of the integrin beta 4 subunit in nonlethal forms of epidermolysis bullosa prevent interaction of beta 4 with plectin.
abstract: The integrin alpha 6 beta 4 plays a crucial role in the assembly and maintenance of hemidesmosomes. Previous work has shown that the recruitment of plectin into hemidesmosomes is dependent on beta 4 and involves a region of the beta 4 cytoplasmic domain, which contains the first two fibronectin (FNIII) repeats and a short region of the connecting segment. Two missense mutations (R1225H and R1281W) in beta 4 that are responsible for nonlethal forms of epidermolysis bullosa are located in the second FNIII repeat. One of them is confined to a loop region that connects two beta strands (EC') whereas the other is located at the N-terminal end of the second FNIII repeat. We here report that these mutations render beta 4 unable to interact with plectin and prevent the localization of plectin in hemidesmosomes. Substitution of a lysine residue (K1279W) that forms part of the same loop as R1281 had no effect on the ability of beta 4 to recruit plectin. Furthermore, we show that an extended loop structure in beta 4, composed of the amino acids DDN (1262--1264), which resembles the RGD integrin-binding loop in fibronectin, is not involved in the binding to plectin. These results further demonstrate that binding of beta 4 to plectin is essential for the proper formation and function of hemidesmosomes and that loss of the interaction between beta 4 and plectin is associated with a mild form of epidermolysis bullosa.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Koster
authors.forename: I
authors.initials: I
authors.lastname: Kuikman
authors.forename: M
authors.initials: M
authors.lastname: Kreft
authors.forename: A
authors.initials: A
authors.lastname: Sonnenberg
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019556:COS Cells; D003593:Cytoplasm; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000378:metabolism*; D022002:Hemidesmosomes / Q000378:metabolism; D039663:Integrin beta4; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D020125:Mutation, Missense; D051190:Plectin; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques; D015003:Yeasts
chemical_list: D015703:Antigens, CD; D018076:DNA, Complementary; D039663:Integrin beta4; D007381:Intermediate Filament Proteins; D051190:Plectin