Three cryo-EM structures of complement C3d-bound α_Mβ₂ reveal an unexpected layer of dynamics for αI-containing integrin receptors.

Abstract

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 α_Mβ₂ 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 α_M internal ligand region that is tightly packed between the α_M 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 α_Mβ₂ in the phagocytotic cup and outline mechanistic models for external ligand-induced activation of α_Mβ₂.