Structural basis for tetraspanin-dependent surface export and adhesive function of integrin α3β1

Abstract

Integrin α3β1 (ITGα3β1) is a member of an integrin subfamily that binds to laminin proteins and promotes attachment of epithelial cells to the basement membrane. ITGα3β1 forms a complex with the tetraspanin CD151, and loss-of-function mutations in both ITGα3 and CD151 cause epidermolysis bullosa, a severe skin blistering disease resulting from a defect in basement membrane attachment. Here, we report the cryoEM structure of an ITGα3β1 complex with CD151 and show that mutation of CD151 at the binding interface disrupts complex formation in cells. Strikingly, CRISPR-mediated knockout of CD151 leads to a variably penetrant ITGα3β1 surface export defect that is restored by re-expression of wild-type but not interface-mutated CD151. Together, these studies define the molecular basis for binding of CD151 to ITGα3β1, and show that CD151 promotes ITGα3β1 surface export, providing a biochemical explanation for the CD151 loss-of-function phenotype in epidermolysis bullosa.