title: Structural insights into Ca2+-calmodulin regulation of Plectin 1a-integrin β4 interaction in hemidesmosomes.
abstract: 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.
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
authors.forename: Jae-Geun
authors.initials: JG
authors.lastname: Song
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
authors.forename: Julius
authors.initials: J
authors.lastname: Kostan
authors.affiliation: Department of Functional Proteomics and Biochemistry, Institute of Biology II and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
authors.forename: Friedel
authors.initials: F
authors.lastname: Drepper
authors.affiliation: Department of Functional Proteomics and Biochemistry, Institute of Biology II and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
authors.forename: Euripedes
authors.initials: E
authors.lastname: de Almeida Ribeiro
authors.affiliation: EMBL-Hamburg c/o DESY, Notkestrasse 85, D-22603 Hamburg, Germany.
authors.forename: Petr V
authors.initials: PV
authors.lastname: Konarev
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
authors.forename: Irina
authors.initials: I
authors.lastname: Grishkovskaya
authors.affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohrgasse 9, A-1030 Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
authors.affiliation: Department of Integrative Biology, Institute of Molecular Genetics of the ASCR, Vídeňská 1083, Prague 4 CZ-14220, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Gregor
authors.affiliation: EMBL-Hamburg c/o DESY, Notkestrasse 85, D-22603 Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: Department of Functional Proteomics and Biochemistry, Institute of Biology II and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Warscheid
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), 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. Electronic address: kristina.djinovic@univie.ac.at.
authors.forename: Kristina
authors.initials: K
authors.lastname: Djinović-Carugo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002147:Calmodulin / Q000737:chemistry*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D022002:Hemidesmosomes / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D039663:Integrin beta4 / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051190:Plectin / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D002147:Calmodulin; D039663:Integrin beta4; C495333:Plec protein, mouse; D051190:Plectin