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Anish U Gupta, Shrey Gupta, Jenna McGowan, Ritu Chakravarti, In silico mapping of 14-3-3ζ and Human TRAF interaction, The Journal of Immunology, Volume 206, Issue 1_Supplement, May 2021, Page 15.09, https://doi.org/10.4049/jimmunol.206.Supp.15.09
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Abstract
Recent advances show that the 14-3-3ζ protein participates in several immune regulations and is a unique regulator of IL-17A signal transduction. The IL-17A signal transduction triggers a 14-3-3ζ-TRAF5 dependent and a 14-3-3ζ-TRAF6 dependent intracellular pathway responsible for producing CXCL-1 and IL-6, respectively. Improved IL-17A signaling blockers are desirable in treating autoimmune diseases such as rheumatoid arthritis and lupus. Due to its unique role, 14-3-3ζ is an attractive target to regulate CXCL-1 and IL-6 levels. The aim of this study is to determine interaction sites between the 14-3-3ζ and TRAF (5 and 6) proteins using bioinformatic tools. We used 6EF5.pdb for 14-3-3ζ, 4GJH.pdb for TRAF5, and ILB6.pdb for TRAF6. Using ZDock, we examined the putative site of the 14-3-3ζ interactions on TRAF (5 and 6) with restrictions and without restrictions. The mapped interacting residues were mutated, and an effect on the interaction with 14-3-3ζ was observed. To further evaluate the interaction quality, we utilized Prodigy to measure the binding energy for several possible structures and narrow down the selected interaction sites further. Results indicate that site 479–485 is the putative target site of the 14-3-3ζ-TRAF5 complex with a ΔG of −10.1 kcal/mol and a Kd of 4.00×10−8. By comparison, residues 483–488 on TRAF6 interact with 14-3-3ζ with a ΔG of −19.1 kcal/mol and a Kd of 9.50×10−15. Our results demonstrate the putative binding sites between the 14-3-3ζ and TRAF (5 and 6) proteins. However, our study has the limitation of using the available but incomplete TRAF structures; therefore, lab studies should be used to confirm these results. Our results provide a rationale to investigate the 14-3-3ζ and TRAF proteins further.
