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Proc. Natl. Acad. Sci. USA, October 24, 2017 vol. 114 no. 43 11422-11427 | doi: 10.1073/pnas.1708688114
Molecular basis for unique specificity of human TRAF4 for platelets GPIbβ and GPVI
Chang Min Kima,b, Young-Jin Sonc, Sunghwan Kimc, Seo Yun Kimd, and Hyun Ho Parka,b,1
aSchool of Natural Science, Department of Chemistry and Biochemistry, Yeungnam University, Gyeongsan 712-749, South Korea;
aSchool of Natural Science, Department of Chemistry and Biochemistry, Yeungnam University, Gyeongsan 712-749, South Korea;
bSchool of Natural Science, Graduate School of Biochemistry, Yeungnam University, Gyeongsan 712-749, South Korea;
cNew Drug Development Center, Daegu-Gyungpook Medical Innovation Foundation, Daegu 701-310, South Korea;
dDepartment of Internal Medicine, Division of Pulmonology, Korea Cancer Center Hospital, Seoul 01812, South Korea
1To whom correspondence should be addressed.
1To whom correspondence should be addressed.
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.
platelet, TRAF4, TRAF domain, glycoprotein Ib, protein structure
platelet, TRAF4, TRAF domain, glycoprotein Ib, protein structure
논문정보
- Research article
- 2017년 10월 (BRIC 등록일 2017-10-17)
- 국내 연구진
- 생명과학 > 구조생물 및 생물물리학
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