Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration.

MCAM/CD146 is an immunoglobulin-superfamily receptor expressed on endothelial cells, immune cells and numerous carcinomas. Although MCAM has long been associated with metastatic progression, recent work has revealed context-dependent inhibitory effects on transendothelial migration, leaving unresolved how MCAM engagement of basement membrane laminins alters cell migration. Here, we report multiple cryo-electron microscopy structures of human MCAM bound to laminin a4. We show MCAM engages laminin on a surface centered on the first two laminin globular domains (LG1-2) and that this epitope directly overlaps with the interface used by α6β1 integrin. Consistent with structural competition, MCAM occupation of laminin α4 abolishes integrin-dependent cell migration. Structure-guided mutation of the MCAM-laminin interface disrupts laminin binding and eliminates MCAM-mediated inhibition. These findings establish that MCAM and integrin compete for a shared interface on laminin α4 and define a structural mechanism by which MCAM occupancy can suppress laminin-dependent migration. The structure resolves a central ambiguity in MCAM biology and provides a framework for developing biologics that selectively modulate pathological cell migration.