Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 16, Pages 10876-10882Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M512472200
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Funding
- NCI NIH HHS [R01 CA031798, R37 CA031798, CA31798] Funding Source: Medline
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alpha(L)beta(2) affinity for intercellular adhesion molecule-1 (ICAM-1) is regulated by the conformation of the alpha(L) I domain, which is in turn controlled by the conformation and orientation of other adjacent domains. Additionally, overall integrin conformation (bent versus straightened) influences the orientation of the I domain and access to its ligands, influencing adhesive efficiency. The open or high affinity I domain conformation supports strong adhesion, whereas the closed, low affinity conformation mediates weak interactions or rolling. We have previously suggested that alpha(L)beta(2) can also exist on the cell surface in an intermediate affinity state. Here we have studied the adhesive properties of integrin alpha(L)beta(2) containing mutant I domains with intermediate affinities for ICAM-1. In an overall bent conformation, the intermediate affinity state of alpha(L)beta(2) is hardly detected by conventional adhesion assays, but robust adhesion is seen when an extended conformation is induced by a small molecule alpha/beta I allo-steric antagonist. Intermediate affinity alpha(L)beta(2) supports more stable rolling than wild-type alpha(L)beta(2) under shear conditions. Moreover, antagonist-induced extension transforms rolling adhesion into firm adhesion in a manner reminiscent of chemokine activation of integrin alpha(L)beta(2). These findings suggest the relevance of intermediate affinity states of alpha(L)beta(2) to the transition between inactive and active states and demonstrate the importance of both I domain affinity and overall integrin conformation for cell adhesion.
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