Structural Superimposition

Abstact

Integrins are heterodimeric membrane proteins acting as mechanosensing receptors. Nine human alpha-subunits contain a ligand binding alphaI domain, but how ligands activate alphaI integrins are not understood. We present cryo-EM structures of the alphaI integrin alpha(M)beta(2) in complex with the C3d ligand. The ligand-bound alphaI domain appears to have two major opposite orientations relative to the beta(2) subunit. Ligand binding induces an ordered conformation of the alpha(M) internal ligand region that is tightly packed between the alpha(M) beta-propeller and the beta(2) betaI-domain. Recognition of the internal ligand induces an open betaI conformation practically identical to that of ligand-bound alphaI-less integrins confirming that ligand binding and signaling are coupled by a universal mechanism across all integrins. Integration of our findings with prior data allows us to propose a model for C3dg/iC3b-bound alpha(M)beta(2) in the phagocytotic cup and outline mechanistic models for external ligand-induced activation of alpha(M)beta(2).