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Vol. 14, Issue 10, 4039-4050, October 2003

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

Sandy H.M. Litjens ^*, Jan Koster ^*, Ingrid Kuikman ^*, Sandra van Wilpe ^*, José M. de Pereda , and Arnoud Sonnenberg ^* 

^* The Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands; Program on Cell Adhesion, The Burnham Institute, La Jolla, California 92037

Submitted May 1, 2003; Revised June 24, 2003; Accepted June 24, 2003
Monitoring Editor: Richard Hynes

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.

Abbreviations used: ABD, actin binding domain; ABS, actin binding sequence; BP, bullous pemphigoid; CH, calponin homology domain, FNIII, fibronectin type III repeat; MD-EBS, muscular dystrophy associated with epidermolysis bullosa simplex; PA-JEB; pyloric atresia associated with junctional epidermolysis bullosa.

Corresponding author. E-mail address: a.sonnenberg{at}nki.nl.

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