Abstract
Although integrin alpha subunit I domains exist in multiple conformations, it is controversial whether integrin beta subunit I-like domains undergo structurally analogous movements of the alpha7-helix that are linked to affinity for ligand. Disulfide bonds were introduced into the beta(3) integrin I-like domain to lock its beta6-alpha7 loop and alpha7-helix in two distinct conformations. Soluble ligand binding, ligand mimetic mAb binding and cell adhesion studies showed that disulfide-bonded receptor alpha(IIb)beta(3)(T329C/A347C) was locked in a low affinity state, and dithiothreitol treatment restored the capability of being activated to high affinity binding; by contrast, disulfide-bonded alpha(IIb)beta(3)(V332C/M335C) was locked in a high affinity state. The results suggest that activation of the beta subunit I-like domain is analogous to that of the alpha subunit I domain, i.e. that axial movement in the C-terminal direction of the alpha7-helix is linked to rearrangement of the I-like domain metal ion-dependent adhesion site into a high affinity conformation.
Highlights
Integrins are large heterodimeric adhesion molecules that convey signals bidirectionally across the plasma membrane [1, 2]
Ligand mimetic mAb binding and cell adhesion studies showed that disulfide-bonded receptor ␣IIb3T329C/A347C was locked in a low affinity state, and dithiothreitol treatment restored the capability of being activated to high affinity binding; by contrast, disulfide-bonded ␣IIb3V332C/M335C was locked in a high affinity state
We have proposed that the change in affinity at the ligand binding site in the I-like domain around its metal ion-dependent adhesion site (MIDAS)1 is communicated to the interface with the hybrid domain on the opposite end of the I-like domain by axial displacement in the C-terminal direction of the I-like domain ␣7-helix [4, 8, 9] (Fig. 1, B and C)
Summary
Integrins are large heterodimeric adhesion molecules that convey signals bidirectionally across the plasma membrane [1, 2]. We have proposed that the change in affinity at the ligand binding site in the I-like domain around its metal ion-dependent adhesion site (MIDAS) is communicated to the interface with the hybrid domain on the opposite end of the I-like domain by axial displacement in the C-terminal direction of the I-like domain ␣7-helix [4, 8, 9] (Fig. 1, B and C). One basis for proposing this mechanism for communicating a change in affinity to the I-like domain MIDAS is that the structurally homologous I domain inserted in some integrin ␣ subunits undergoes a similar piston-like movement of its C-terminal ␣7-helix, which regulates the affinity of its MIDAS for ligand [2]. The data uniquely support the proposal that downward movement of the ␣7-helix induces I-like domain activation and demonstrate that ␣ I and  I-like domains are activated by structurally analogous mechanisms
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