Structure of fish TRAF4 and its implication in TRAF4-mediated immune cell and platelet signaling

• Published in: Fish & shellfish immunology Vol. 132; p. 108462
• Main Authors: Kim, Chang Min, Jang, Hyunseok, Hong, Eunmi, Lee, Jun Hyuck, Park, Hyun Ho
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2023
• Subjects: Animals; Blood Platelets; Cold adaptivity; Crystal structure; Fishes - genetics; Fishes - metabolism; Humans; Innate immunity; Protein Binding; Protein-protein interaction; Proteins - metabolism; Signal Transduction; TNF Receptor-Associated Factor 4 - chemistry; TNF Receptor-Associated Factor 4 - genetics; TRAF4; Innate immunity; Protein-protein interaction; TRAF4; Cold adaptivity; Crystal structure
• ISSN: 1050-4648; 1095-9947
• DOI: 10.1016/j.fsi.2022.108462

Due to an increasing interest in immunity and signal transduction in teleost fish, important key signaling molecules associated with the immune response, including TRAF molecules, have been recently cloned and characterized. To better understand the role of TRAF4 in fish immune signaling and compare it with the human system, our study cloned the TRAF4 gene from the Antarctic yellowbelly rockcod Notothenia coriiceps (ncTRAF4) and purified the protein. Here, we report the first crystal structure of teleost fish TRAF4. Based on biochemical characterization, our findings elucidated the mechanisms through which signaling molecules gain cold adaptivity. Additionally, we identified a platelet receptor GPIbβ homolog in N. coriiceps (ncGPIbβ) and found that the “RRFERLFKEARRTS” region of this homolog directly binds to ncTRAF4, indicating that ncTRAF4 also recognizes the “RLXA” motif for receptor interactions and further TARF4-mediated cellular signaling. Collectively, our findings provide novel insights into the mechanisms of TRAF4-mediated immune cell and platelet signaling in fish and the structural flexibility-mediated cold adaptiveness of signaling molecules.
•The trimeric structure of TRAF4 from Notathenia coriiceps was elucidated.•The cold-adaptivity was explained based on the structure of ncTRAF4.•The “RRFERLFKEARRTS” region of a platelet receptor GPIbβ homolog in N. coriiceps directly binds to ncTRAF4.•The tentative mode of ncTRAF4 interactions with its various receptors for immune cell signaling was provided.