Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618371
Title: The structure and function of integrins
Author: Douglass, Wendy A.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1997
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Abstract:
Integrins are a family of αβ heterodimeric cell surface glycoproteins formed by the noncovalent association of a specific integrin α and β subunit. At present 16 different integrin α subunits and 8 different integrin β subunits have been identified, which can associate in various combinations to produce over 20 different integrin αβ heterodimeric receptors. The leukocyte integrins LFA-1 (αLβ2, CD11a/CD18), Mac-1 (αMβ2, CD11b/CD18) and p150,95 (αXβ2, CD11c/CD18) are formed by the non-covalent association of the αL, αM or αX subunits with the β2 subunit. In order to determine the regions of the β2 subunit which are involved in its heterodimeric interaction with the αL, αM and αX subunits, eight variant β2 subunits were analysed for their ability to form LFA-1, Mac-1 and p150,95 heterodimeric complexes. Three chimeric β2/β1 subunits: β2V1, β2V12 and β2NS1, and three analogous chimeric β2/β7 subunits: β2V7, β2V72 and β2NS7, as well as a soluble and a truncated β2 subunit: β2sol and β2tr, were studied. All of the variant β2 subunits retained the ability to associate with the αL subunit, suggesting that the N-terminal 436 amino acids of the β2 subunit are sufficient to provide the specificity for LFA-1 heterodimer formation. In contrast, all the β2 variants associated inefficiently with the αM and αX subunits, suggesting that the heterodimeric interactions between the α and β subunits in Mac-1 and p150,95 are more extensive, and perhaps more complicated than those in LFA-1. The ability of the modified LFA-1 heterodimers formed with the variant β2 subunits to bind to the LFA-1 ligand ICAM-1 was also studied. All of the modified LFA-1 receptors retained the ability to bind to ICAM-1, suggesting that in LFA-1, the ICAM-1 binding site in the β2 subunit must be located within its N-terminal 436 amino acids. In addition, unlike the wildtype LFA-1 receptor, all of the modified LFA-1 receptors were constitutively active with respect to ICAM-1 binding. It therefore appears that specific interactions between different regions of the β2 subunit are required to constrain the LFA-1 receptor in its inactive, resting state, and that disruption of any one of these intramolecular interactions results in release of the receptor into its high affinity ligand binding conformation. This "constraint model" for the regulation of LFA-1 activity may also be applicable to other integrins. Analysis of a number of mutant β2 subunits carrying leukocyte adhesion deficiency (LAD) mutations, and their ability to form LFA-1, Mac-1 and p150,95 heterodimers, provided results consistent with those obtained with the variant β2 subunits.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.618371  DOI: Not available
Keywords: Integrins ; Structure
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