Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, 1230 York Ave, New York, NY 10065, USA.
Department of Immunology and Microbiology and Department of Chemistry, Scripps Research, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Chem Commun (Camb). 2022 Jun 8;58(46):6598-6601. doi: 10.1039/d2cc01903e.
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.
为了进一步了解 NOD2 识别二肽基肽（MDP）的机制，我们评估了在哺乳动物细胞中形成 Arf6-MDP-NOD2 复合物所涉及的关键性质。我们发现，保守的 Arf 芳香三肽对于与 MDP-NOD2 的结合至关重要。Arf6 的 N-豆蔻酰化和 NOD2 的 S-棕榈酰化突变也会破坏 Arf6-MDP-NOD2 复合物的形成。值得注意的是，脂质修饰的 MDP（L18-MDP）增加了 Arf6-NOD2 的组装。我们的研究结果表明，Arf6 的募集可能解释了脂质化 MDP 类似物活性增强的原因，而膜靶向可能是开发新一代 NOD2 激动剂的关键。
