Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 40, Pages 30370-30374Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.C110.134247
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Funding
- National Institutes of Health, NHLBI [P01 HL073311, R01 HL096062]
- American Heart Association [10SDG2610277]
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Kindlins are essential for integrin activation in cell systems and do so by working in a cooperative fashion with talin via their direct interaction with integrin beta cytoplasmic tails (CTs). Kindlins interact with the membrane-distal NxxY motif, which is distinct from the talin-binding site within the membrane-proximal NxxY motif. The Tyr residues in both motifs can be phosphorylated, and it has been suggested that this modification of the membrane-proximal NxxY motif negatively regulates interaction with the talin head domain. However, the influence of Tyr phosphorylation of the membrane-distal NxxY motif on kindlin binding is unknown. Using mutational analyses and phosphorylated peptides, we show that phosphorylation of the membrane-distal NITY759 motif in the beta(3) CT disrupts kindlin-2 recognition. Phosphorylation of this membrane-distal Tyr also disables the ability of kindlin-2 to coactivate the integrin. In direct binding studies, peptides corresponding to the non-phosphorylated beta(3) CT interacted well with kindlin-2, whereas the Tyr(759)-phosphorylated peptide failed to bind kindlin-2 with measurable affinity. These observations indicate that transitions between the phosphorylated and non-phosphorylated states of the integrin beta(3) CT determine reactivity with kindlin-2 and govern the role of kindlin-2 in regulating integrin activation.
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