The mechanical stability of epithelial cells, which protect organisms from harmful external factors, is maintained by hemidesmosomes via the interaction between plectin 1a (P1a) and integrin α6β4. Binding of calcium-calmodulin (Ca(2+)-CaM) to P1a together with phosphorylation of integrin β4 disrupts this complex, resulting in disassembly of hemidesmosomes. We present structures of the P1a actin binding domain either in complex with the N-ter lobe of Ca(2+)-CaM or with the first pair of integrin β4 fibronectin domains. Ca(2+)-CaM binds to the N-ter isoform-specific tail of P1a in a unique manner, via its N-ter lobe in an extended conformation. Structural, cell biology, and biochemical studies suggest the following model: binding of Ca(2+)-CaM to an intrinsically disordered N-ter segment of plectin converts it to an α helix, which repositions calmodulin to displace integrin β4 by steric repulsion. This model could serve as a blueprint for studies aimed at understanding how Ca(2+)-CaM or EF-hand motifs regulate F-actin-based cytoskeleton.

Department of Biochemistry and Cell Biology Max F Perutz Laboratories University of Vienna Dr Bohrgasse 9 A 1030 Vienna Austria

Department of Functional Proteomics and Biochemistry Institute of Biology 2 and BIOSS Centre for Biological Signaling Studies University of Freiburg Schaenzlestrasse 1 D 79104 Freiburg Germany

Department of Integrative Biology Institute of Molecular Genetics of the ASCR Vídeňská 1083 Prague 4 CZ 14220 Czech Republic

Department of Structural and Computational Biology Max F Perutz Laboratories University of Vienna Vienna Biocenter Campus Vienna Biocenter 5 A 1030 Vienna Austria

Department of Structural and Computational Biology Max F Perutz Laboratories University of Vienna Vienna Biocenter Campus Vienna Biocenter 5 A 1030 Vienna Austria; Department of Biochemistry Faculty of Chemistry and Chemical Technology University of Ljubljana Aškerčeva 5 SI 1000 Ljubljana Slovenia

EMBL Hamburg c o DESY Notkestrasse 85 D 22603 Hamburg Germany

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Mechanics of cell sheets: plectin as an integrator of cytoskeletal networks

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PDB
4Q57, 4Q58, 4Q59