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Integrin On, Integrin Off

Integrin receptors play a fundamental role in cell movement and adhesion by providing a physical connection between the cytoskeleton and extracellular matrix to enable bidirectional signaling through the cell membrane. Two important integrin ligands inside the cell are talin and Dok1, both of which bind to the cytoplasmic tail of the integrin β3 subunit but act in opposite fashion; talin is a positive regulator of integrin activation whereas Dok1 is a negative regulator.

X-ray model of Dok1 complexed with the integrin β tail shows that phosphorylation of integrin Tyr747 enhances Dok1 binding through hydrogen bonding to a pair of arginines.

In this Paper of the Week, Camilla Oxley and colleagues used both x-ray crystallography and NMR spectroscopy to investigate the molecular interactions of these competing ligands. They found that Dok1 and talin both bind to the integrin β3 NPLY motif, but unlike talin, Dok1 does not interact with the membrane-proximal region upon binding and therefore does not initiate integrin activation. Heteronuclear single quantum coherence (HSQC) experiments revealed that talin has 3 times as much affinity for the integrin tail as Dok1, but upon phosphorylation of integrin Tyr⁷⁴⁷, binding preference shifts dramatically to Dok1. These results suggest that tyrosine 747 phosphorylation acts as a switch to regulate integrin activation.

FOOTNOTES

See referenced article, J. Biol. Chem. 2008, 283, 5420-5426

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