Three cryo-EM structures of complement C3d-bound αMβ2 reveal an unexpected layer of dynamics for αI-containing integrin receptors.

Integrins are heterodimeric membrane proteins acting as mechanosensing receptors. Nine human α-subunits contain a ligand binding αI domain, but how ligands activate αI integrins are not understood. We present cryo-EM structures of the αI integrin αMβ2 in complex with the C3d ligand. The ligand-bound αI domain appears to have two major opposite orientations relative to the β2 subunit. Ligand binding induces an ordered conformation of the αM internal ligand region that is tightly packed between the αM β-propeller and the β2 βI-domain. Recognition of the internal ligand induces an open βI conformation practically identical to that of ligand-bound αI-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 αMβ2 in the phagocytotic cup and outline mechanistic models for external ligand-induced activation of αMβ2.