TY - JOUR
T1 - The integrin α-subunit leg extends at a Ca2+-dependent epitope in the thigh/genu interface upon activation
AU - Xie, Can
AU - Shimaoka, Motomu
AU - Xiao, Tsan
AU - Schwab, Pascale
AU - Klickstein, Lloyd B.
AU - Springer, Timothy A.
PY - 2004/10/26
Y1 - 2004/10/26
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.0406680101
DO - 10.1073/pnas.0406680101
M3 - Article
C2 - 15494438
AN - SCOPUS:7444240182
SN - 0027-8424
VL - 101
SP - 15422
EP - 15427
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -