Flexible Structure of Peptide-Bound Filamin A Mechanosensor Domain Pair 20–21

摘要

Filamins (FLNs) are large, multidomain actin cross-linking proteins with diverse functions.Besides regulating the actin cytoskeleton, they serve as important links between the extracellularmatrix and the cytoskeleton by binding cell surface receptors, functioning as scaffoldsfor signaling proteins, and binding several other cytoskeletal proteins that regulate celladhesion dynamics. Structurally, FLNs are formed of an amino terminal actin-bindingdomain followed by 24 immunoglobulin-like domains (IgFLNs). Recent studies have demonstratedthat myosin-mediated contractile forces can reveal hidden protein binding sites inthe domain pairs IgFLNa18–19 and 20–21, enabling FLNs to transduce mechanical signalsin cells. The atomic structures of these mechanosensor domain pairs in the resting state areknown, as well as the structures of individual IgFLN21 with ligand peptides. However, littleexperimental data is available on how interacting protein binding deforms the domain pairstructures. Here, using small-angle x-ray scattering-based modelling, x-ray crystallography,and NMR, we show that the adaptor protein migfilin-derived peptide-bound structure ofIgFLNa20–21 is flexible and adopts distinctive conformations depending on the presence orabsence of the interacting peptide. The conformational changes reported here may be commonfor all peptides and may play a role in the mechanosensor function of the site.