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Integrins are transmembrane proteins involved in hemostasis, wound healing,immunity and cancer. In response to intracellular signals and ligand binding,integrins adopt different conformations: the bent (resting) form; theintermediate extended form; and the ligand-occupied active form. An integrinundergoing such conformational dynamics is the heterodimeric platelet receptoralphaIIbbeta3. Although the dramatic rearrangement of the overall structure ofalphaIIbbeta3 during the activation process is potentially related to changesin the protein secondary structure, this has not been investigated so far in amembrane environment. Here we examine the Mn2+- and drug-induced activation ofalphaIIbbeta3 and the impact on the structure of this protein reconstitutedinto liposomes. By quartz crystal microbalance with dissipation monitoring andactivation assays we show that Mn2+ induces binding of theconformation-specific antibody PAC-1, which only recognizes the extended,active integrin. Circular dichroism spectroscopy reveals, however, thatMn2+-treatment does not induce major secondary structural changes ofalphaIIbbeta3. Similarly, we found that treatment with clinically relevantdrugs (e.g. quinine) led to the activation of alphaIIbbeta3 without significantchanges in protein secondary structure. Molecular dynamics simulation studiesrevealed minor local changes in the beta-sheet probability of severalextracellular domains of the integrin. Our experimental setup represents a newapproach to study transmembrane proteins, especially integrins, in a membraneenvironment and opens a new way for testing drug binding to integrins underclinically relevant conditions.

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes