Discrete functional motifs reside within the cytoplasmic tail of αV integrin subunit

Thomas A Haas

doi:10.1160/TH07-08-0498

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(01): 96-107
DOI: 10.1160/TH07-08-0498

Platelets and Blood Cells

Schattauer GmbH

Discrete functional motifs reside within the cytoplasmic tail of α_V integrin subunit

Thomas A Haas

¹Department of Anatomy and Cell Biology and Molecular Design Research Group, College of Medicine, University of Saskatchewan, Saskatoon, Canada

› Author Affiliations

Abstract

Summary

Previous studies have demonstrated that cell-permeable cytoplasmic tail (CT) α_IIβ peptides can modulate the activation of α_IIbb₃.As α_VCT contains an α_IIβ homologous region, a series of cell-permeable α_V and α_IIb peptides were generated to determine if α_V CT can modulate the activation of β3 integrins in comparison to α_IIb, and to identify the minimal bioactive sequences in α_V CT. Using NMR structures and molecular models as guides, the initial peptides for study encompassed the α_IIβ homologous sequences of α_V CT (α_V(987–1006); V-1), its amino-terminus (α_V(987–993);V-2), a turn motif (α_V(993–1001);V-3), the carboxyl- terminus (α_V(999–1006); V-4), and corresponding homologous α_IIb peptides. Treatment of platelets and α_Vβ₃-expressing cells with the peptides revealed that IIb-1 inhibited α_IIβ₃ activation and V-1 inhibited α_Vβ₃ activation, but not vice versa. The inhibitory capacity of these peptides was mapped to the central turn-motif region which was encompassed by V-3, but only partially by IIb-3.V-2 and IIb-2 activated both β₃ integrins, while V-4 and IIb-4 were inactive. The use of truncation and mutant peptides confirmed the importance of the turn motif for inhibitory activity and identified the side-chain of α_V(Q1001) as a critical inhibitory residue. The difference in the integrin inhibitory capacity of α_V and α_IIb peptides and their capacity to influence the assembly of kinases with integrin CTs, reveals a possible divergence in the regulatory control of the two β₃ integrins.

Keywords

GP IIb/IIIa - Integrins - antiplatelet agents - fibrinogen / fibrin

Full Text

References

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