Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI

Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11422-11427. doi: 10.1073/pnas.1708688114. Epub 2017 Oct 10.

Abstract

Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290∼470) in complex with a peptide from the GPIbβ receptor (amino acid residues 177∼181). The GPIbβ peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg-Leu-X-Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-β receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.

Keywords: TRAF domain; TRAF4; glycoprotein Ib; platelet; protein structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calorimetry / methods
  • Models, Molecular
  • Platelet Glycoprotein GPIb-IX Complex / chemistry*
  • Platelet Glycoprotein GPIb-IX Complex / metabolism
  • Platelet Membrane Glycoproteins / chemistry*
  • Platelet Membrane Glycoproteins / metabolism
  • Protein Conformation
  • Signal Transduction
  • TNF Receptor-Associated Factor 4 / chemistry*
  • TNF Receptor-Associated Factor 4 / metabolism

Substances

  • Platelet Glycoprotein GPIb-IX Complex
  • Platelet Membrane Glycoproteins
  • TNF Receptor-Associated Factor 4
  • TRAF4 protein, human
  • platelet membrane glycoprotein VI

Associated data

  • PDB/5YC1