Integrin {beta}3 phosphorylation dictates its complex with the Shc phosphotyrosine-binding (PTB) domain

J Biol Chem. 2010 Nov 5;285(45):34875-84. doi: 10.1074/jbc.M110.159087. Epub 2010 Aug 25.

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 β(3), 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 β(3)integrin cytoplasmic tail (CT). We show that this complex is primarily defined by the phosphorylation state of the integrin C-terminal Tyr(759), which fits neatly into the classical PTB pocket of Shc. In addition, we have identified a novel binding interface which concurrently accommodates phosphorylated Tyr(747) of the highly conserved NPXY motif of β(3). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Integrin beta3 / chemistry*
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism
  • Phosphorylation
  • Phosphotyrosine
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Shc Signaling Adaptor Proteins / chemistry*
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism

Substances

  • Integrin beta3
  • Multiprotein Complexes
  • Peptides
  • Shc Signaling Adaptor Proteins
  • Phosphotyrosine

Associated data

  • PDB/2L1C