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Integrin {beta}3 phosphorylation dictates its complex with the Shc phosphotyrosine-binding (PTB) domain
Lalit Deshmukh1, Vitaliy Gorbatyuk, Olga Vinogradova
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269-3092, USA.
The Journal of Biological Chemistry
|August 27, 2010
Summary
Adaptor protein Shc binds to integrin β(3) cytoplasmic tail, revealing the structural basis for integrin outside-in signaling. This interaction is crucial for the mitogen-activated protein kinase (MAPK) pathway.
Area of Science:
- Cellular signaling
- Structural biology
- Molecular interactions
Background:
- Adaptor protein Shc is vital for mitogen-activated protein kinase (MAPK) signaling.
- Integrins mediate outside-in signaling, but the structural basis of Shc interaction is unclear.
- Shc recognizes tyrosine-phosphorylated integrin β(3) to initiate signaling.
Purpose of the Study:
- To elucidate the structural basis of the Shc phosphotyrosine-binding (PTB) domain interaction with the bi-phosphorylated integrin β(3) cytoplasmic tail (CT).
- To understand how this complex mediates integrin outside-in signaling.
Main Methods:
- Detailed structural analysis of the Shc PTB domain in complex with the β(3) integrin CT.
- Crystallography and structural comparison.
Main Results:
- The Shc PTB domain binds the β(3) integrin CT via phosphorylation at Tyr(759), fitting into the PTB pocket.
- A novel binding interface accommodates phosphorylated Tyr(747) within the conserved NPXY motif.
- This structure is the first snapshot of an integrin CT bound to a signaling mediator.
Conclusions:
- The phosphorylation state of Tyr(759) is key for Shc PTB domain binding.
- A dual-binding mechanism involving Tyr(759) and Tyr(747) defines the interaction.
- Structural insights reveal Shc PTB domain specificity and its role in integrin signaling.
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