A Structural Hypothesis for the Transition between Bent and Extended Conformations of the Leukocyte β2 Integrins

Integrins mediate cell adhesion in response to activation signals that trigger conformational changes within their ectodomain. It is thought that a compact bent conformation of the molecule represents its physiological low affinity state and extended conformations its active state. We have determine...

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Published in:The Journal of biological chemistry 2007-10, Vol.282 (41), p.30198-30206
Main Authors: Shi, MinLong, Foo, Shen Yun, Tan, Suet-Mien, Mitchell, Edward P., Law, S.K. Alex, Lescar, Julien
Format: Article
Language:English
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Summary:Integrins mediate cell adhesion in response to activation signals that trigger conformational changes within their ectodomain. It is thought that a compact bent conformation of the molecule represents its physiological low affinity state and extended conformations its active state. We have determined the structure of two integrin fragments of the β2 subunit. The first structure, consisting of the plexin-semaphorin-integrin domain, hybrid, integrin-epidermal growth factor 1 (I-EGF1), and I-EGF2 domains (PHE2), showed an L-shaped conformation with the bend located between the I-EGF1 and I-EGF2 domains. The second structure, which includes, in addition, the I-EGF3 domain, showed an extended conformation. The major reorientation of I-EGF2 with respect to the other domains in the two structures is accompanied by a change of torsion angle of the disulfide bond between Cys461-Cys492 by 180° and the conversion of a short α-helix (residues Ser468-Cys475) into a flexible coil. Based on the PHE2 structure, we introduced a disulfide bond between the plexin-semaphorin-integrin domain and I-EGF2 domains in the β2 subunit. The resultant αLβ2 integrin (leukocyte function-associated antigen-1) variant was locked in a bent state and could not be detected with the monoclonal antibody KIM127 in Mg2+/EGTA. However, it retained the binding activity to ICAM-1. These results provide a structural hypothesis for our understanding of the transition between the resting and active states of leukocyte function-associated antigen-1.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M701670200