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

Proceedings of the National Academy of Sciences of the United States of America
Chang Min KimHyun Ho Park

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.

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Citations

Oct 26, 2018·Proceedings of the National Academy of Sciences of the United States of America·Gang CaiXiaoxia Li
Aug 22, 2018·International Journal of Molecular Sciences·Eijaz Ahmed BhatHyun Ho Park
Sep 15, 2018·Frontiers in Immunology·Hyun H Park
Apr 25, 2020·International Journal of Molecular Sciences·Chang Min Kim, Hyun Ho Park
May 11, 2021·Archives of Pharmacal Research·Hyun Ho Park

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