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

Abstract

Small linear motif targeting protein interacting domains called 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 μM 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. Seven of the PDZ-containing proteins among binders of the SARS-CoV-2 proteins E, 3a or N affect significantly 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.

Quantitative fragmentomics allow affinity mapping of interactomes

“…1101 The PDZ-PBM interactome is also prone to pathological perturbations such as viral infection and cancer (James & Roberts, 2016). Viral proteins bearing functional PBMs are found notably in HPV and HTLV oncoviruses as well as in HBV, WNV and coronaviruses including MERS or SARS-CoV2 (Javier & Rice, 2011) (Banks et al, 2012) (James & Roberts, 2016) (Sámano-Sánchez & Gibson, 2020) (Jimenez-Guardeño et al, 2014) (Caillet-Saguy et al, 2021).…”

ACE2 interaction with cytoplasmic PDZ protein enhances SARS-CoV-2 invasion

“…Given the role of DPP4 in glucose and amino acid homeostasis and the prevalence of type II diabetes associated with Covid-19 (Valencia et al, 2020), DPP4 (CD26) is especially intriguing considering that its carboxy tail resides in the extracellular space (Yan et al, 2007). In addition to host cell surface receptors including ACE2, NRP1, and DPP4, viral proteins E, 3A, and N from SARS-CoV-2 itself also possess PDZ-binding motifs (Caillet-Saguy et al, 2021), suggesting PDZ interaction possibly defines SARS-CoV-2 invasion from either intra-or extracellular sides of infected host cells. The related outcomes from these characterizations may delineate a broad role for PDZ proteins in SARS/MERS infections and help us better understand the pathogenic mechanisms of SARS coronavirus and, consequently, serve as a foundation for developing new therapeutic strategies to restrict SARS-CoV-2 infection.…”

Domain Analysis and Motif Matcher (DAMM): A Program to Predict Selectivity Determinants in <em>Monosiga brevicollis</em> PDZ Domains Using Human PDZ Data

“…The best studied example includes PDZ domain targeting by oncoproteins in human papillomaviruses, but several other viruses, including influenza, human immunodeficiency virus (HIV), and coronaviruses also target PDZ domains [5,[33][34][35][36][37][38]. For example, proteins in the SARS-CoV-2 proteome, which causes COVID-19 disease, interact with and bind several PDZ domains during infection [39][40][41][42]. The trafficking of angiotensin-converting enzyme 2 (ACE2) receptor), which is targeted by SARS-CoV-2, contains a PDZ-binding mofit at its C-terminus (sequence: DVQTSF, motif residues are underlined) and is also regulated by PDZ domains [43].…”