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Cysteine allostery and autoinhibition govern human STING oligomer functionality

Nature Chemical Biology. 2025-10; 
Rebecca Chan, Xujun Cao, Sabrina L Ergun, Evert Njomen, Stephen R Lynch, Christopher Ritchie, Benjamin Cravatt, Lingyin Li
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Peptide Synthesis Lysates prepared as described in respective protocols were separated on a SurePage Bis–Tris polyacrylamide gel (GenScript) and transferred to a nitrocellulose membrane using the semi-dry iBlot2 system (Inv itrogen). ... ontaining STING, TBS was replaced with buffer containing STING CTD purified as described above and concentrated to 1.5 mM, with the appropriate addition of unlabeled CTT7 (GenScript) or 2’,3’-cGAMP (synthesized in-house according to ref.41). NMR d Get A Quote
Protein Electrophoresis and Western Get A Quote

摘要

The stimulator of interferon genes (STING) innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, no inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human STING activation are crucial for inhibition of downstream signaling. Here we report that C91 palmitoylation is not universally necessary for human STING signaling. Instead, evolutionarily-conserved C64 is basally palmitoylated and is crucial for preventing unproductive STING oligomerization. The effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at C148. Together, dynamic e... More

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