BPS2026 – Structural insights into integrin conformational dynamics underlying leukocyte rolling and adhesion

Integrins are heterodimeric receptors that mediate cell-cell and cell-matrix interactions, regulating diverse processes such as adhesion, migration, and signaling. Among them, α4 integrins play a central role in leukocyte extravasation by mediating rolling and firm adhesion of leukocytes to vascular endothelium, primarily through recognition of their natural ligands. Despite their critical function in immune responses, the structural basis of α4 integrins binding to cell adhesion molecules has remained unresolved. Here, we present multiple cryo-electron microscopy (cryo-EM) structures of human α4 integrins: ligand free closed conformations and open conformations bound to a conformation-specific antibody fragment as well as to ligands. These structures reveal the molecular determinants of ligand specificity and conformational regulation, providing long awaited structural insights into α4 integrin function. Our findings establish a framework for understanding leukocyte adhesion mediated by integrins and may guide the development of improved therapeutic strategies targeting integrin signaling.