title: The molecular basis of filamin binding to integrins and competition with talin.
abstract: The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.
authors.affiliation: Biocenter Oulu, Department of Biochemistry, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Tiila
authors.initials: T
authors.lastname: Kiema
authors.forename: Yatish
authors.initials: Y
authors.lastname: Lad
authors.forename: Pengju
authors.initials: P
authors.lastname: Jiang
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Oxley
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Baldassarre
authors.forename: Kate L
authors.initials: KL
authors.lastname: Wegener
authors.forename: Iain D
authors.initials: ID
authors.lastname: Campbell
authors.forename: Jari
authors.initials: J
authors.lastname: Ylänne
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002154:Calpain / Q000378:metabolism; D003285:Contractile Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D064448:Filamins; D039641:Integrin beta Chains / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D016608:Talin / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D039641:Integrin beta Chains; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D016608:Talin; D002154:Calpain