PDZ-Containing Proteins Targeted by the ACE2 Receptor

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a main receptor for SARS-CoV-2 entry to the host cell. Indeed, the first step in viral entry is the binding of the viral trimeric spike (S) protein to ACE2. Abundantly present in human epithelial cells of many organs, ACE2 is also expressed in the human brain. ACE2 is a type I membrane protein with an extracellular N-terminal peptidase domain and a C-terminal collectrin-like domain that ends with a single transmembrane helix and an intracellular 44-residue segment. This C-terminal segment contains a PDZ-binding motif (PBM) targeting protein-interacting domains called PSD-95/Dlg/ZO-1 (PDZ). Here, we identified the human PDZ specificity profile of the ACE2 PBM using the high-throughput holdup assay and measuring the binding intensities of the PBM of ACE2 against the full human PDZome. We discovered 14 human PDZ binders of ACE2 showing significant binding with dissociation constants’ values ranging from 3 to 81 μM. NHERF, SHANK, and SNX27 proteins found in this study are involved in protein trafficking. The PDZ/PBM interactions with ACE2 could play a role in ACE2 internalization and recycling that could be of benefit for the virus entry. Interestingly, most of the ACE2 partners we identified are expressed in neuronal cells, such as SHANK and MAST families, and modifications of the interactions between ACE2 and these neuronal proteins may be involved in the neurological symptoms of COVID-19.

Cerebral microvascular complications associated with SARS-CoV-2 infection: How did it occur and how should it be treated?

“…ACE2 is a transmembrane receptor with specific enzymatical properties and is expressed in epithelial cells of various human organs, including the lung, heart, kidney, intestine, brain, and also endothelium [67] , [68] , [69] . Studies have shown that this receptor promotes viral replication of SARS-CoV in several organs and confirmed the presence of human ACE2 in cerebrovascular endothelium [70] .…”

Structural basis for targeting the human T-cell leukemia virus Tax oncoprotein and syntenin-1 interaction using a small molecule

“…Interestingly, the conserved C -terminal PBM motifs of these viral proteins highly correlate with viral pathogenicity, independently of their substantial differences in genome content (RNA and DNA viruses) or mode of infection (acute and persistent families of viruses). Other examples include syntenin-1 and PTPN13, both able to interact with distant viral proteins such as the HTLV Tax-1 (this study), but also with the coronaviral E, 3A and N proteins (Caillet-Saguy et al, 2021; Caillet-Saguy and Wolff, 2021; Jimenez-Guardeño et al, 2014). These pan-viral interactors may thus constitute ideal drug targets for the discovery of broad-spectrum antiviral inhibitors.…”

SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling

“…ZO-1 possesses a PDZ domain, which is responsible for binding and interaction with other proteins (Saras & Heldin, 1996; Giepmans & Moolenaar, 1998). Interestingly, ACE2 possesses a PDZ-binding domain (Dasgupta & Bandyopadhyay, 2021; Caillet-Saguy & Wolff, 2021), and it has been suggested that epitopes of viral proteins, such as 1–60: M1Lys60 and 241–300: Ala240-Glu300 could directly bind to ZO-1 and VCAM-1 PDZ domains, thus suggesting a possible alternative route of CNS entry. We found ZO-1 and claudin-5 protein levels to be increased after 24 h of infection in HBMECs and this increase is consistent with what our group recently demonstrated with S1 treatment (Torices et al, 2021).…”