Importance of force linkage in mechanochemistry of adhesion receptors

Nathan S. Astrof, Azucena Salas, Motomu Shimaoka, Jian Feng Chen, Timothy A. Springer

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The α subunit-inserted (I) domain of integrin α Lβ2 [lymphocyte function-associated antigen-1 (LFA-1)] binds to intercellular adhesion molecule-1 (ICAM-1). The C- and N-termini of the α 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 α I domain conformation, a 7 Å downward, axial displacement of C-terminal helix α7 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 α 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 αL 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 α 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 α and β 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.

Original languageEnglish
Pages (from-to)15020-15028
Number of pages9
JournalBiochemistry
Volume45
Issue number50
DOIs
StatePublished - 19 Dec 2006
Externally publishedYes

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