Journal
CHEMICAL COMMUNICATIONS
Volume 58, Issue 46, Pages 6598-6601Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2cc01903e
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Funding
- NCCIH NRSA Ruth Kirschstein Fellowship [F32AT10087]
- Rainin Foundation Health Grant [20201459]
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This study evaluated the key properties involved in the formation of the Arf6-MDP-NOD2 complex in mammalian cells and found that the conserved Arf aromatic triad is crucial for binding to MDP-NOD2. Mutation of Arf6 N-myristoylation and NOD2 S-palmitoylation also disrupted the formation of the complex. Lipid-modified MDP was observed to increase Arf6-NOD2 assembly, suggesting that membrane targeting may be important in developing next-generation NOD2 agonists.
To further understand the mechanisms of muramyl dipeptide (MDP) sensing by NOD2, we evaluated key properties involved in the formation of the Arf6-MDP-NOD2 complex in mammalian cells. We found that the conserved Arf aromatic triad is crucial for binding to MDP-NOD2. Mutation of Arf6 N-myristoylation and NOD2 S-palmitoylation also abrogated the formation of the Arf6-MDP-NOD2 complex. Notably, lipid-modified MDP (L18-MDP) increased Arf6-NOD2 assembly. Our results indicate recruitment of Arf6 may explain enhanced activity of lipidated MDP analogues and membrane targeting may be important in developing next-generation NOD2 agonists.
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