An integrin α_IIbβ₃ intermediate affinity state mediates biomechanical platelet aggregation

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Integrins are vital membrane receptors involved in cell adhesion and mechanosensing.
• Understanding integrin structure-function is critical for cell biology and translational medicine.
• The precise states and transitions of integrins, particularly α_IIbβ₃, are not fully elucidated.

Purpose of the Study:

• To investigate the mechanical properties and conformational states of integrin α_IIbβ₃.
• To identify novel states of integrin α_IIbβ₃ beyond the known inactive and active states.
• To elucidate the role of mechanical forces in integrin activation and platelet aggregation.

Main Methods:

• Utilized a fluorescence dual biomembrane force probe for precise mechanical stimulation.
• Employed microfluidics and cone-and-plate rheometry to apply controlled forces to platelets.
• Analyzed integrin α_IIbβ₃ conformation, ligand affinity, and bond lifetimes under mechanical stress.

Main Results:

• Identified a novel intermediate state of integrin α_IIbβ₃ with intermediate ectodomain conformation, ligand affinity, and bond lifetimes.
• Demonstrated that ligand engagement of glycoprotein (GP) Ibα induces this intermediate state via a mechanosignalling pathway.
• Showed that the intermediate state potentiates outside-in mechanosignalling, facilitating transition to the active state and promoting platelet aggregation.

Conclusions:

• Revealed distinct state transitions of integrin α_IIbβ₃ in response to biomechanical and biochemical stimuli.
• Established the existence and function of an intermediate integrin α_IIbβ₃ state in mechanical affinity maturation.
• Highlighted the significance of the intermediate state in promoting biomechanical platelet aggregation, with implications for thrombosis and hemostasis.