Rolling adhesion through an extended conformation of integrin alphaLbeta2 and relation to alpha I and beta I-like domain interaction.
In vivo, beta(2) integrins and particularly alpha(L)beta(2) (LFA-1) robustly support firm adhesion of leukocytes, but can also cooperate with other molecules in supporting rolling adhesion. Strikingly, a small molecule alpha/beta I-like allosteric antagonist, XVA143, inhibits LFA-1-dependent firm adhesion, while at the same time it enhances adhesion in shear flow and rolling both in vitro and in vivo. XVA143 appears to induce the extended conformation of integrins as shown by increased activation epitope exposure. Fab to the beta(2) I-like domain converts firm adhesion to rolling adhesion, but does not enhance adhesion. Residue alpha(L)-Glu-310 in the linker following the I domain is critical for communication to the beta(2) I-like domain, rolling, integrin extension, and activation by Mn(2+) of firm adhesion. The results demonstrate the importance of integrin extension in rolling, and suggest that rolling and firm adhesion are mediated by extended conformations of alpha(L)beta(2) that differ in the affinity of the alpha(L) I domain for ICAM-1.
Salas
Azucena
A
The CBR Institute for Biomedical Research, Department of Pathology, 200 Longwood Avenue, Boston, MA 02115 USA.
Shimaoka
Motomu
M
Kogan
Avi N
AN
Harwood
Charlotte
C
von Andrian
Ulrich H
UH
Springer
Timothy A
TA
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D039423:Integrin alpha1 / Q000737:chemistry / Q000276:immunology*; D019012:Integrin beta1 / Q000737:chemistry / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D036904:Leukocyte Rolling / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008968:Molecular Conformation
D039423:Integrin alpha1; D019012:Integrin beta1; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1