Structural insights into integrin α₅β₁ opening by fibronectin ligand

Area of Science:

• Biochemistry
• Structural Biology
• Cell Biology

Background:

• Integrin α5β1 is a crucial fibronectin receptor involved in cell migration.
• Conformational changes in integrin α5β1 upon fibronectin binding are essential for cell-tissue connections but mechanistically unclear.

Purpose of the Study:

• To elucidate the structural mechanism of integrin α5β1 activation by fibronectin.
• To determine the conformational states of resting and ligand-bound integrin α5β1.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
• Biochemical analyses to assess ligand-binding affinity.

Main Results:

• Cryo-EM structures of human α5β1 with fibronectin (3.1 Å) and resting α5β1 (4.6 Å) were obtained.
• The α5β1-fibronectin complex structure reveals simultaneous interactions at multiple sites, inducing integrin opening via helix α1 translocation.
• Resting α5β1 adopts a half-bent conformation, challenging previous models.
• Ligand-binding affinity is enhanced by manganese ions (Mn2+) and does not strictly depend on conformation; integrin opening is ligand-induced.

Conclusions:

• The study provides atomic-level insights into integrin α5β1 activation by fibronectin.
• Integrin α5β1 opening is a ligand-induced process, not solely dependent on a fully bent resting state.
• Findings clarify the molecular basis of cell-fibronectin interactions crucial for cell migration.