Filamins in mechanosensing and signaling

Abstract

Filamins are essential, evolutionarily conserved, modular, multidomain, actin-binding proteins that organize the actin cytoskeleton and maintain extracellular matrix connections by anchoring actin filaments to transmembrane receptors. By cross-linking and anchoring actin filaments, filamins stabilize the plasma membrane, provide cellular cortical rigidity, and contribute to the mechanical stability of the plasma membrane and the cell cortex. In addition to binding actin, filamins interact with more than 90 other binding partners including intracellular signaling molecules, receptors, ion channels, transcription factors, and cytoskeletal and adhesion proteins. Thus, filamins scaffold a wide range of signaling pathways and are implicated in the regulation of a diverse array of cellular functions including motility, maintenance of cell shape, and differentiation. Here, we review emerging structural and functional evidence that filamins are mechanosensors and/or mechanotransducers playing essential roles in helping cells detect and respond to physical forces in their local environment.

Figure 1

Schematic representation of human filamin. The N-terminal actin-binding domain containing two calponin-homology domains (CH1 and CH2) is followed by 24 Ig repeats of ~96 amino acids each. The Ig repeats are interrupted by two hinge regions (H1 and H2) and fold into anti-parallel β-sheets. The C-terminal 24^th repeat is the dimerization domain. Repeats 1-15 make up rod domain 1, while repeats 16-24 make up rod domain 2. Domain pairs (16-17, 18-19 and 20-21) are boxed in gray.

Figure 2

Details of the interaction between IgFLNa17 (blue) and the cytoplasmic peptide of platelet glycoprotein Ibα (Green) (85). Letters A-G indicate the β-stands of the filamin domain forming two sheets: GFC (above) and ABED (below). Note that the GPIbα forms an extra strand next to the strand C. The hydrophopic residues of the ligand extending towards the groove between stands C and D are shown as sticks and marked with numbers 1-5 (see Table 1).

Figure 3

Mechanism of the ligand binding site opening in IgFLNa18-19 based on steered molecular dynamics simulations (92). The A-strand of IgFLNa18 unzips from the CD-face of IgFLNa19 under pulling forces that are much lower than those required for Ig-domain unfolding. The positions of some of the hydrogen bonds connecting the A-stand are indicated with dotted lines. Pulling-forces to the C-terminus and N-terminus are indicated by black and red arrows, respectively.