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

Salt bridge interactions within the β2 integrin α7 helix mediate force‐induced binding and... The functional performance of the αI domain α7 helix in β2 integrin activation depends on the allostery of the α7 helix, which axially slides down; therefore, it is critical to elucidate what factors regulate the allostery. In this study, we determined that there were two conservative salt bridge interaction pairs that constrain both the upper and bottom ends of the α7 helix. Molecular dynamics (MD) simulations for three β2 integrin members, lymphocyte function‐associated antigen‐1 (LFA‐1; αLβ2), macrophage‐1 antigen (Mac‐1; αMβ2) and αxβ2, indicated that the magnitude of the salt bridge interaction is related to the stability of the αI domain and the strength of the corresponding force‐induced allostery. The disruption of the salt bridge interaction, especially with double mutations in both salt bridges, significantly reduced the force‐induced allostery time for all three members. The effects of salt bridge interactions of the αI domain α7 helix on β2 integrin conformational stability and allostery were experimentally validated using Mac‐1 constructs. The results demonstrated that salt bridge mutations did not alter the conformational state of Mac‐1, but they did increase the force‐induced ligand binding and shear resistance ability, which was consistent with MD simulations. This study offers new insight into the importance of salt bridge interaction constraints of the αI domain α7 helix and external force for β2 integrin function. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Febs Journal Wiley

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

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Publisher
Wiley
Copyright
Copyright © 2018 Federation of European Biochemical Societies
ISSN
1742-464X
eISSN
1742-4658
D.O.I.
10.1111/febs.14335
Publisher site
See Article on Publisher Site

Abstract

The functional performance of the αI domain α7 helix in β2 integrin activation depends on the allostery of the α7 helix, which axially slides down; therefore, it is critical to elucidate what factors regulate the allostery. In this study, we determined that there were two conservative salt bridge interaction pairs that constrain both the upper and bottom ends of the α7 helix. Molecular dynamics (MD) simulations for three β2 integrin members, lymphocyte function‐associated antigen‐1 (LFA‐1; αLβ2), macrophage‐1 antigen (Mac‐1; αMβ2) and αxβ2, indicated that the magnitude of the salt bridge interaction is related to the stability of the αI domain and the strength of the corresponding force‐induced allostery. The disruption of the salt bridge interaction, especially with double mutations in both salt bridges, significantly reduced the force‐induced allostery time for all three members. The effects of salt bridge interactions of the αI domain α7 helix on β2 integrin conformational stability and allostery were experimentally validated using Mac‐1 constructs. The results demonstrated that salt bridge mutations did not alter the conformational state of Mac‐1, but they did increase the force‐induced ligand binding and shear resistance ability, which was consistent with MD simulations. This study offers new insight into the importance of salt bridge interaction constraints of the αI domain α7 helix and external force for β2 integrin function.

Journal

Febs JournalWiley

Published: Jan 1, 2018

Keywords: ; ; ; ;

References

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