Abstract:
:Previous studies have demonstrated that cell-permeable cytoplasmic tail (CT) alpha(II)beta peptides can modulate the activation of alpha(IIb)b(3). As alpha(V) CT contains an alpha(II)beta homologous region, a series of cell-permeable alpha(V) and alpha(IIb) peptides were generated to determine if alpha(V) CT can modulate the activation of beta(3) integrins in comparison to alpha(IIb), and to identify the minimal bioactive sequences in alpha(V) CT. Using NMR structures and molecular models as guides, the initial peptides for study encompassed the alpha(II)beta homologous sequences of alpha(V) CT (alpha(V)(987-1006); V-1), its amino-terminus (alpha(V)(987-993); V-2), a turn motif (alpha(V)(993-1001); V-3), the carboxyl-terminus (alpha(V)(999-1006); V-4), and corresponding homologous alpha(IIb) peptides. Treatment of platelets and alpha(V)beta(3)-expressing cells with the peptides revealed that IIb-1 inhibited alpha(IIb)beta(3) activation and V-1 inhibited alpha(V)beta(3) 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 beta(3) 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 alpha(V)(Q1001) as a critical inhibitory residue. The difference in the integrin inhibitory capacity of alpha(V) and alpha(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 beta(3) integrins.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Haas TAdoi
10.1160/TH07-08-0498subject
Has Abstractpub_date
2008-01-01 00:00:00pages
96-107issue
1eissn
0340-6245issn
2567-689Xpii
08010096journal_volume
99pub_type
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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