Structural insights into Ca2+-calmodulin regulation of Plectin 1a-integrin ?4 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 ?6?4. Binding of calcium-calmodulin (Ca(2+)-CaM) to P1a together with phosphorylation of integrin ?4 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 ?4 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 ? helix, which repositions calmodulin to displace integrin ?4 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.

SUBMITTER: Song JG 

PROVIDER: S-EPMC4353693 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature