Specificity of Binding of the Plectin Actin-binding Domain to 4 Integrin

Plectin is a major component of the cytoskeleton and links the intermediate filament system to hemidesmosomes by binding to the integrin 4 subunit. Previously, a binding site for 4 was mapped on the actin-binding domain (ABD) of plectin and binding of 4 and F-actin to plectin was shown to be mutually exclusive. Here we show that only the ABDs of plectin and dystonin bind to 4, whereas those of other actin-binding proteins do not. Mutations of the ABD of plectin-1C show that Q131, R138, and N149 are critical for tight binding of the ABD to 4. These residues form a small cavity, occupied by a well-ordered water molecule in the crystal structure. The 4 binding pocket partly overlaps with the actin-binding sequence 2 (ABS2), previously shown to be essential for actin binding. Therefore, steric interference may render binding of 4 and F-actin to plectin mutually exclusive. Finally, we provide evidence indicating that the residues preceding the ABD in plectin-1A and -1C, although unable to mediate binding to 4 themselves, modulate the binding activity of the ABD for 4. These studies demonstrate the unique property of the plectin-ABD to bind to both F-actin and 4, and explain why several other ABD-containing proteins that are expressed in basal keratinocytes are not recruited into hemidesmosomes.