Host PDZ‐containing proteins targeted by SARS‐CoV‐2

• DOI: 10.1111/febs.15881
• Publication Date: 2021-04-17T17:11:43Z
• Authors: Célia Caillet‐Saguy; Fabien Durbesson; Veronica V. Rezelj; Gergö Gogl; Quang Dinh Tran; Jean‐Claude Twizere; Marco Vignuzzi; Renaud Vincentelli; Nicolas Wolff
• Keywords: 0301 basic medicine; 570; PDZ-containing protein; [SDV]Life Sciences [q-bio]; Protein Tyrosine Phosphatase, Non-Receptor Type 13; 610; Kinesins; PDZ Domains; Myosins; human PDZ library; Virus Replication; Viroporin Proteins; 03 medical and health sciences; Viral Envelope Proteins; Coronavirus Nucleocapsid Proteins; Humans; Protein Interaction Domains and Motifs; SARS-CoV-2; PDZ-binding motif; COVID-19; Virus Internalization; 3. Good health; viral proteins E; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; Host-Pathogen Interactions; Zonula Occludens-1 Protein; viral replication; 3A and N; Carrier Proteins; Protein Binding

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.