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The functional performance of 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 of LFA-1 (αL β2 ), Mac-1 (αM β2 ) and αx β2 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 the double mutations in both salt bridges, significantly reduced 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 increased the force-induced ligand binding and shear resistance ability, which was consistent with MD simulations. This study offers new insight into the importance of the salt bridge interaction constraints of the αI domain α7 helix and the external force for β2 integrin function. This article is protected by copyright. All rights reserved.
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An integrin alpha subunit that primarily associates with INTEGRIN BETA1 or INTEGRIN BETA4 to form laminin-binding heterodimers. Integrin alpha6 has two alternatively spliced isoforms: integrin alpha6A and integrin alpha6B, which differ in their cytoplasmic domains and are regulated in a tissue-specific and developmental stage-specific manner.
An integrin beta subunit of approximately 85-kDa in size which has been found in INTEGRIN ALPHAIIB-containing and INTEGRIN ALPHAV-containing heterodimers. Integrin beta3 occurs as three alternatively spliced isoforms, designated beta3A-C.
The first DNA-binding protein motif to be recognized. Helix-turn-helix motifs were originally identified in bacterial proteins but have since been found in hundreds of DNA-BINDING PROTEINS from both eukaryotes and prokaryotes. They are constructed from two alpha helices connected by a short extended chain of amino acids, which constitute the "turn." The two helices are held at a fixed angle, primarily through interactions between the two helices. (From Alberts et al., Molecular Biology of the Cell, 3d ed, p408-9)
An integrin alpha subunit that binds COLLAGEN and LAMININ though its I domain. It combines with INTEGRIN BETA1 to form the heterodimer INTEGRIN ALPHA1BETA1.
The alpha subunits of integrin heterodimers (INTEGRINS), which mediate ligand specificity. There are approximately 18 different alpha chains, exhibiting great sequence diversity; several chains are also spliced into alternative isoforms. They possess a long extracellular portion (1200 amino acids) containing a MIDAS (metal ion-dependent adhesion site) motif, and seven 60-amino acid tandem repeats, the last 4 of which form EF HAND MOTIFS. The intracellular portion is short with the exception of INTEGRIN ALPHA4.