title: Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation.
abstract: Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined.
authors.affiliation: Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California Berkeley, 208A Stanley Hall #1762, Berkeley, CA 94704-1762, USA. mofrad@berkeley.edu.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Truong
authors.forename: Hengameh
authors.initials: H
authors.lastname: Shams
authors.forename: Mohammad R K
authors.initials: MR
authors.lastname: Mofrad
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D001696:Biomechanical Phenomena; D064448:Filamins / Q000737:chemistry / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D039661:Integrin beta3 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055672:Static Electricity; D016608:Talin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D064448:Filamins; D039661:Integrin beta3; D016608:Talin