title: Flexible Structure of Peptide-Bound Filamin A Mechanosensor Domain Pair 20-21.
abstract: Filamins (FLNs) are large, multidomain actin cross-linking proteins with diverse functions. Besides regulating the actin cytoskeleton, they serve as important links between the extracellular matrix and the cytoskeleton by binding cell surface receptors, functioning as scaffolds for signaling proteins, and binding several other cytoskeletal proteins that regulate cell adhesion dynamics. Structurally, FLNs are formed of an amino terminal actin-binding domain followed by 24 immunoglobulin-like domains (IgFLNs). Recent studies have demonstrated that myosin-mediated contractile forces can reveal hidden protein binding sites in the domain pairs IgFLNa18-19 and 20-21, enabling FLNs to transduce mechanical signals in cells. The atomic structures of these mechanosensor domain pairs in the resting state are known, as well as the structures of individual IgFLN21 with ligand peptides. However, little experimental data is available on how interacting protein binding deforms the domain pair structures. 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 of IgFLNa20-21 is flexible and adopts distinctive conformations depending on the presence or absence of the interacting peptide. The conformational changes reported here may be common for all peptides and may play a role in the mechanosensor function of the site.
authors: Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
authors: Jonne
authors: J
authors: Seppälä
authors: Program in Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Helena
authors: H
authors: Tossavainen
authors: Program in Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Nebojsa
authors: N
authors: Rodic
authors: Program in Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Perttu
authors: P
authors: Permi
authors: Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
authors: Ulla
authors: U
authors: Pentikäinen
authors: Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
authors: Jari
authors: J
authors: Ylänne
mesh_terms: D000199:Actins / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray / Q000379:methods; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D064448:Filamins / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D009218:Myosins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D064448:Filamins; D008024:Ligands; D010455:Peptides; D011994:Recombinant Proteins; D009218:Myosins