Molecular basis for unique specificity of human TRAF4 for platelets GPIb beta and GPVI

作者：Kim Chang Min; Son Young Jin; Kim Sunghwan; Kim Seo Yun; Park Hyun Ho^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(43): 11422-11427.

DOI：10.1073/pnas.1708688114

• platelet
• TRAF4
• TRAF domain
• glycoprotein Ib
• protein structure

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 similar to 470) in complex with a peptide from the GPIb beta receptor (amino acid residues 177 similar to 181). The GPIb beta 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-beta 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.

• 出版日期2017-10-24