title: Importance of force linkage in mechanochemistry of adhesion receptors.
abstract: The alpha subunit-inserted (I) domain of integrin alphaLbeta2 [lymphocyte function-associated antigen-1 (LFA-1)] binds to intercellular adhesion molecule-1 (ICAM-1). The C- and N-termini of the alpha I domain are near one another on the "lower" face, opposite the metal ion-dependent adhesion site (MIDAS) on the "upper face". In conversion to the open alpha I domain conformation, a 7 A downward, axial displacement of C-terminal helix alpha7 is allosterically linked to rearrangement of the MIDAS into its high-affinity conformation. Here, we test the hypothesis that when an applied force is appropriately linked to conformational change, the conformational change can stabilize adhesive interactions that resist the applied force. Integrin alpha I domains were anchored to the cell surface through their C- or N-termini using type I or II transmembrane domains, respectively. C-terminal but not N-terminal anchorage robustly supported cell rolling on ICAM-1 substrates in shear flow. In contrast, when the alphaL I domain was mutationally stabilized in the open conformation with a disulfide bond, it mediated comparable levels of firm adhesion with type I and type II membrane anchors. To exclude other effects as the source of differential adhesion, these results were replicated using alpha I domains conjugated through the N- or C-terminus to polystyrene microspheres. Our results demonstrate a mechanical feedback system for regulating the strength of an adhesive bond. A review of crystal structures of integrin alpha and beta subunit I domains and selectins in high- and low-affinity conformations demonstrates a common mechanochemical design in which biologically applied tensile force stabilizes the more extended, high-affinity conformation.
authors.affiliation: The CBR Institute for Biomedical Research, Department of Anesthesia and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Astrof
authors.forename: Azucena
authors.initials: A
authors.lastname: Salas
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.forename: JianFeng
authors.initials: J
authors.lastname: Chen
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D006801:Humans; D039423:Integrin alpha1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D036904:Leukocyte Rolling / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D019038:Platelet Glycoprotein GPIb-IX Complex; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D039423:Integrin alpha1; D039641:Integrin beta Chains; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D018799:Intercellular Adhesion Molecule-1