Salt bridge interactions within the β₂ integrin α₇ helix mediate force-induced binding and shear resistance ability

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The αI domain's α7 helix is crucial for β2 integrin activation.
• Allosteric regulation of the α7 helix is key to integrin function.
• Understanding factors controlling α7 helix allostery is critical.

Purpose of the Study:

• To identify factors regulating the allostery of the α7 helix in β2 integrins.
• To investigate the role of salt bridge interactions in αI domain stability and allostery.
• To experimentally validate the impact of salt bridge disruptions on β2 integrin function.

Main Methods:

• Molecular dynamics (MD) simulations of LFA-1, Mac-1, and αxβ2 integrins.
• Analysis of salt bridge interactions at the α7 helix.
• Experimental validation using Mac-1 constructs with mutated salt bridges.

Main Results:

• Two conserved salt bridges constrain the α7 helix.
• Salt bridge strength correlates with αI domain stability and allosteric response.
• Disrupting salt bridges significantly reduced force-induced allostery.
• Mutations increased force-induced ligand binding and shear resistance without altering conformation.

Conclusions:

• Salt bridge interactions are critical regulators of β2 integrin allostery.
• These interactions are essential for β2 integrin conformational stability and force-induced responses.
• External force and salt bridge constraints interplay to modulate β2 integrin function.