Institut Pasteur, Unité Récepteurs-Canaux, UMR CNRS 3571, Paris, France.
AFMB, UMR CNRS 7257, Marseille, France.
FEBS J. 2021 Sep;288(17):5148-5162. doi: 10.1111/febs.15881. Epub 2021 May 1.
Small linear motifs targeting protein interacting domains called PSD-95/Dlg/ZO-1 (PDZ) have been identified at the C terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins E, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E, 3A, and N showing significant interactions with dissociation constants values ranging from 3 to 82 μm. Six of them (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) are also recognized by SARS-CoV while three (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection. Among the binders of the SARS-CoV-2 proteins E, 3a, or N, seven significantly affect viral replication under knock down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 and to conceive effective anti-coronaviral agents for therapeutic purposes.
已在严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）蛋白 E、3a 和 N 的 C 末端鉴定出针对称为 PDZ-95/Dlg/ZO-1（PDZ）的蛋白质相互作用域的小型线性基序。使用针对完整人 PDZome 的高通量亲和剖析方法，我们鉴定出 16 种 SARS-CoV-2 蛋白 E、3A 和 N 的人 PDZ 结合物，其与解离常数的相互作用值范围为 3 至 82 μm。其中 6 种（TJP1、PTPN13、HTRA1、PARD3、MLLT4、LXN2）也被 SARS-CoV 识别，而 3 种（NHERF1、MAST2、RADIL）则是 SARS-CoV-2 E 蛋白特有的。这些 SARS-CoV-2 蛋白伙伴中的大多数都参与细胞连接/极性，并且可能与病毒感染期间免疫反应的逃避机制有关。在受感染细胞中下调基因表达时，SARS-CoV-2 蛋白 E、3a 或 N 的结合物中有 7 种可显著影响病毒复制。这种鉴定 SARS-CoV-2 潜在靶标人类蛋白的 PDZ 分析有助于了解 COVID19 的多因素严重性，并为治疗目的构思有效的抗冠状病毒药物。
