The integrin α-subunit leg extends at a Ca2+-dependent epitope in the thigh/genu interface upon activation

Can Xie, Motomu Shimaoka, Tsan Xiao, Pascale Schwab, Lloyd B. Klickstein, Timothy A. Springer

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Abstract

Two activation-dependent Abs to the integrin αL-subunit were used to study conformational rearrangement of αLβ 2 on the cell surface. Activation lowered the concentration of Ca2+ required for maximal expression of each epitope. Each Ab requires the Ca2+-binding loop in the integrin genu and nearby species-specific residues in the thigh domain. Key thigh residues are shielded from Ab in the bent integrin conformation by the α-subunit calf-1 domain and the nearby bent β leg, suggesting that extension at the genu is required for epitope exposure. Activating stimuli and α/β I-like small molecule antagonists demonstrate that exposure of epitopes in the integrin α- and β-subunit legs is coordinate during integrin activation. A coordinating residue donated by the calf-1 domain is as important as Ca 2+ for mAb binding. Together with inspection of the Ca2+ structure, this result suggests that the genu/ calf-1 interface is maintained in integrin activation, and that extension occurs by a rearrangement at the thigh/genu interface.

Original languageEnglish (US)
Pages (from-to)15422-15427
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number43
DOIs
StatePublished - Oct 26 2004

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