Structural insights into integrin α 5 β 1 opening by fibronectin ligand

• Published in: Science advances 2021-05, Vol.7 (19)
• Main Authors: Schumacher, Stephanie, Dedden, Dirk, Nunez, Roberto Vazquez, Matoba, Kyoko, Takagi, Junichi, Biertümpfel, Christian, Mizuno, Naoko
• Format: Article
• Language: English
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abe9716

Integrin α β is a major fibronectin receptor critical for cell migration. Upon complex formation, fibronectin and α β undergo conformational changes. While this is key for cell-tissue connections, its mechanism is unknown. Here, we report cryo-electron microscopy structures of native human α β with fibronectin to 3.1-angstrom resolution, and in its resting state to 4.6-angstrom resolution. The α β -fibronectin complex revealed simultaneous interactions at the arginine-glycine-aspartate loop, the synergy site, and a newly identified binding site proximal to adjacent to metal ion-dependent adhesion site, inducing the translocation of helix α1 to secure integrin opening. Resting α β adopts an incompletely bent conformation, challenging the model of integrin sharp bending inhibiting ligand binding. Our biochemical and structural analyses showed that affinity of α β for fibronectin is increased with manganese ions (Mn ) while adopting the half-bent conformation, indicating that ligand-binding affinity does not depend on conformation, and α β opening is induced by ligand-binding.