Integrin β3 phosphorylation dictates its complex with the Shc phosphotyrosine-binding (PTB) domain

Abstract

Adaptor protein Shc plays a key role in mitogen-activated protein kinase (MAPK) signaling pathway, which can be mediated through a number of different receptors including integrins. By specifically recognizing the tyrosine-phosphorylated integrin β3, Shc has been shown to trigger integrin outside-in signaling, although the structural basis of this interaction remains nebulous. Here we present the detailed structural analysis of Shc phosphotyrosine-binding (PTB) domain in complex with the bi-phosphorylated β3integrin cytoplasmic tail (CT). Weshow that this complex is primarily defined by the phosphorylation state of the integrin C-terminal Tyr759, which fits neatly into the classical PTB pocket of Shc. In addition, we have identified a novel binding interface which concurrently accommodates phosphorylated Tyr747 of the highly conserved NPXY motif of β3. The structure represents the first snapshot of an integrin cytoplasmic tail bound to a target for mediating the outside-in signaling. Detailed comparison with the known Shc PTB structure bound to a target TrkA peptide revealed some significant differences, which shed new light upon the PTB domain specificity. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.