Song Jae-Geun, Kostan Julius, Drepper Friedel, Knapp Bettina, de Almeida Ribeiro Euripedes, Konarev Petr V, Grishkovskaya Irina, Wiche Gerhard, Gregor Martin, Svergun Dmitri I, Warscheid Bettina, Djinović-Carugo Kristina
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 Functional Proteomics and Biochemistry, Institute of Biology II and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
Structure. 2015 Mar 3;23(3):558-570. doi: 10.1016/j.str.2015.01.011. Epub 2015 Feb 19.
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.
上皮细胞可保护生物体免受有害外部因素的侵害，其机械稳定性由半桥粒通过网蛋白1a（P1a）与整合素α6β4之间的相互作用来维持。钙调蛋白（Ca(2+)-CaM）与P1a的结合以及整合素β4的磷酸化会破坏这种复合物，导致半桥粒解体。我们展示了P1a肌动蛋白结合结构域与Ca(2+)-CaM的N端叶或与整合素β4纤连蛋白结构域的第一对结构域形成复合物的结构。Ca(2+)-CaM以独特的方式通过其处于伸展构象的N端叶与P1a的N端异构体特异性尾部结合。结构、细胞生物学和生物化学研究提出了以下模型：Ca(2+)-CaM与网蛋白的内在无序N端片段结合，将其转化为α螺旋，该螺旋重新定位钙调蛋白，通过空间排斥取代整合素β4。该模型可为旨在了解Ca(2+)-CaM或EF手基序如何调节基于F-肌动蛋白的细胞骨架的研究提供蓝图。
