Structural Insights into Ca2+-Calmodulin Regulation of Plectin 1a-Integrin β4 Interaction in Hemidesmosomes

Abstract

SummaryThe 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 (Ca2+-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 Ca2+-CaM or with the first pair of integrin β4 fibronectin domains. Ca2+-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 Ca2+-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 Ca2+-CaM or EF-hand motifs regulate F-actin-based cytoskeleton.

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…The majority of previous studies on integrin α6β4 have focused on the hemidesmosome in various epithelial cells. Integrin α6β4‐plectin binding is essential for the formation and stabilization of the hemidesmosome, an anchoring structure that mediates the attachment of epithelial cells to the cell substratum . Podocytes are specialized epithelial cells whose foot processes attach to the GBM.…”

Structural Insights into Cargo Recognition by the Yeast PTS1 Receptor

“…The analysis of LC-MS/MS datasets with the aim to identify cross-linked peptides was performed as described previously (27) with only slight modifications. For the search of potentially photo-cross-linked products, pairs of peptides, each according to the enzyme specificity of trypsin with up to two missed cleavages, were generated from amino acid sequences of the recombinant proteins, and cross-links between the given site of pBpa and any amino acid position in the target peptide were considered.…”

The molecular architecture of hemidesmosomes as revealed by super-resolution microscopy

“…However, it is unknown how the different hemidesmosome components are spatially organized relative to one another. Neither is it known how the keratin intermediate filaments are anchored to hemidesmosomes in cultured keratinocytes, or whether they are directly involved in the organization of the hemidesmosome structure (Song et al, 2015;Seltmann et al, 2015).…”