REGULATION OF PLATELET INTEGRIN FUNCTION

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

Integrins reside on cell surfaces in an equilibrium between inactive and active conformations. Thus, shifting[unreadable] the equilibrium towards the inactive conformation will decrease integrin activity, whereas stabilizing the[unreadable] activated conformation will increase activity. Integrin transmembrane domains interact heteromerically when[unreadable] integrins are inactive and homomerically following activation. Accordingly, physiologic processes that[unreadable] destabilize heteromeric interactions or stabilize homomeric interactions would be expected to induce integrin[unreadable] activation. The work proposed in this application continues our examination of the relationship between[unreadable] transmembrane domain interactions and integrin function by integrating cell biological, molecular biological,[unreadable] and biophysical methods. The studies focus on the platelet integrin alpha-llb-beta3. In Specific Aim 1. we will[unreadable] characterize the helical interfaces that mediate the heteromeric and homomeric interactions of the alpha-llb and[unreadable] beta3 transmembrane domains. We have shown that a GxxxG motif in the alpha-llb transmembrane helix is[unreadable] essential for its homomeric interactions. The motif also likely participates in the heteromeric interaction of[unreadable] alpha-llb with beta3, but the identity of other alpha-llb residues that participate in this association are not known. The[unreadable] information available about the beta3 residues involved in its heteromeric and homomeric interactions is limited[unreadable] and conflicting. The data obtained from the proposed studies will be used to construct models of integrin[unreadable] transmembrane domain oligomers using computational methods and to determine the relative contribution of[unreadable] heteromeric and homomeric interactions in regulating alpha-llb-beta3 function using transfected cells. Lastly, the[unreadable] participation of cytoplasmic domain sequences in stabilizing transmembrane domain interactions will be[unreadable] considered. Specific Aim 2 is based on observations that synthetic peptides can be designed to modulate[unreadable] the assembly of transmembrane proteins. The proposed experiments will provide additional insight into the[unreadable] role of TM helix interactions in alpha-llb-beta3 activation and proof of principle for the use of synthetic transmembrane[unreadable] domain peptides as anti-thrombotic agents.