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

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.

Keywords: 3A and N; PDZ-binding motif; PDZ-containing protein; SARS-CoV-2; human PDZ library; viral proteins E; viral replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / genetics*
  • COVID-19 / virology
  • Carrier Proteins / genetics
  • Coronavirus Nucleocapsid Proteins / genetics
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Kinesins / genetics
  • Myosins / genetics
  • PDZ Domains / genetics*
  • Protein Binding / genetics
  • Protein Interaction Domains and Motifs / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics
  • SARS-CoV-2 / genetics*
  • SARS-CoV-2 / pathogenicity
  • Viral Envelope Proteins / genetics
  • Viroporin Proteins / genetics
  • Virus Internalization
  • Virus Replication / genetics
  • Zonula Occludens-1 Protein / genetics


  • 3a protein, SARS-CoV
  • AFDN protein, human
  • Carrier Proteins
  • Coronavirus Nucleocapsid Proteins
  • E protein, SARS coronavirus
  • Lnx2 protein, human
  • TJP1 protein, human
  • Viral Envelope Proteins
  • Viroporin Proteins
  • Zonula Occludens-1 Protein
  • PTPN13 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13
  • Myosins
  • Kinesins