Abstract
Previous evidence suggests that interactions between integrin cytoplasmic domains regulate integrin activation. We have constructed and validated recombinant structural mimics of the heterodimeric alpha(IIb)beta(3) cytoplasmic domain. The mimics elicited polyclonal antibodies that recognize a combinatorial epitope(s) formed in mixtures of the alpha(IIb) and beta(3) cytoplasmic domains but not present in either isolated tail. This epitope(s) is present within intact alpha(IIb)beta(3), indicating that interaction between the tails can occur in the native integrin. Furthermore, the combinatorial epitope(s) is also formed by introducing the activation-blocking beta(3)(Y747A) mutation into the beta(3) tail. A membrane-distal heptapeptide sequence in the alpha(IIb) tail ((997)RPPLEED) is responsible for this effect on beta(3). Membrane-permeant palmitoylated peptides, containing this alpha(IIb) sequence, specifically blocked alpha(IIb)beta(3) activation in platelets. Thus, this region of the alpha(IIb) tail causes the beta(3) tail to resemble that of beta(3)(Y747A) and suppresses activation of the integrin.
Highlights
The integrin family of adhesion receptors is essential for the development and functioning of multicellular animals [1]
Previous evidence suggests that interactions between integrin cytoplasmic domains regulate integrin activation
Membrane-permeant palmitoylated peptides, containing this ␣IIb sequence, blocked ␣IIb3 activation in platelets. This region of the ␣IIb tail causes the 3 tail to resemble that of 3(Y747A) and suppresses activation of the integrin
Summary
The integrin family of adhesion receptors is essential for the development and functioning of multicellular animals [1]. Integrin ␣ and  subunits contain a remarkably conserved 7–10-residue motif near the junction of the transmembrane and cytoplasmic domains (membrane-proximal segment) [6]. Interactions of membrane distal portions of the  cytoplasmic domain with proteins such as talin appear to be important in integrin activation. In addition to a role for the membrane-distal portion of the  cytoplasmic domain, interactions between integrin ␣ and  subunit cytoplasmic tails may regulate activation. Complementary mutations in the ␣ and  subunits suggest that these activating mutations disrupt an interaction between the highly conserved membrane-proximal portions of the ␣ and  cytoplasmic tails [18]. There is evidence to suggest that an interaction between integrin ␣ and  tails regulates activation
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