Structural determinants driving the binding process between PDZ domain of wild type human PALS1 protein and SLiM sequences of SARS-CoV E proteins

Cascio, Ettore Lo; Toto, Angelo; Babini, Gabriele; Maio, Flavio De; Sanguinetti, Maurizio; Mordente, Alvaro; Longa, S. Della; Arcovito, Alessandro

doi:10.1016/j.csbj.2021.03.014

Cited by 12 publications

(16 citation statements)

References 50 publications

(34 reference statements)

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“…Modeling of the SARS-CoV-2 E protein [ 22 ] suggests that E can form a broadly cation selective ion channel with dynamic open and closed states, and therefore may act as a viroporin similar to that of the SARS-CoV-1 E protein [ 25 , 37 ]. Although the genome of SARS-CoV-2 only shares about 80% identity with that of SARS-CoV-1, the ECT of the SARS-CoV-2 E protein, including the DLLV core motif and adjacent amino acids, are highly conserved with those of SARS-CoV-1 E protein ( Fig 1 ) [ 13 , 15 , 30 , 31 ]. Sequence alignment of the SARS-CoV-1 and SARS-CoV-2 E proteins ( Fig 1 ) highlight the sequence similarities and the putative PBM located at the ECT in both proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the SARS-CoV-1 E protein was shown to interact with the PDZ domain of TJ protein PALS1, resulting in mislocalization of PALS1 and delayed formation of TJs in a renal model [27]. In subsequent studies, the C-terminal sequences of SARS-CoV-2 E protein were also predicted to bind to the PDZ domain of PALS1 [28][29][30]. While the PDZ domain of PALS1 was not included in our screening array (Fig 2), PALS1 was identified as a weak interactor with SARS-CoV-2 E protein in a recent report [40].…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, the extreme C-terminal (ECT) sequence of the E protein of SARS-CoV-2 is similar to that of SARS-CoV-1, suggesting that it may also interact with specific host PDZdomain bearing proteins via this putative PBM. Indeed, recent studies showed that the SARS--CoV-2 E protein exhibited an increased affinity for PALS1 [13,[28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1

et al. 2021

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Newly emerged SARS-CoV-2 is the cause of an ongoing global pandemic leading to severe respiratory disease in humans. SARS-CoV-2 targets epithelial cells in the respiratory tract and lungs, which can lead to amplified chloride secretion and increased leak across epithelial barriers, contributing to severe pneumonia and consolidation of the lungs as seen in many COVID-19 patients. There is an urgent need for a better understanding of the molecular aspects that contribute to SARS-CoV-2-induced pathogenesis and for the development of approaches to mitigate these damaging pathologies. The multifunctional SARS-CoV-2 Envelope (E) protein contributes to virus assembly/egress, and as a membrane protein, also possesses viroporin channel properties that may contribute to epithelial barrier damage, pathogenesis, and disease severity. The extreme C-terminal (ECT) sequence of E also contains a putative PDZ-domain binding motif (PBM), similar to that identified in the E protein of SARS-CoV-1. Here, we screened an array of GST-PDZ domain fusion proteins using either a biotin-labeled WT or mutant ECT peptide from the SARS-CoV-2 E protein. Notably, we identified a singular specific interaction between the WT E peptide and the second PDZ domain of human Zona Occludens-1 (ZO1), one of the key regulators of TJ formation/integrity in all epithelial tissues. We used homogenous time resolve fluorescence (HTRF) as a second complementary approach to further validate this novel modular E-ZO1 interaction. We postulate that SARS-CoV-2 E interacts with ZO1 in infected epithelial cells, and this interaction may contribute, in part, to tight junction damage and epithelial barrier compromise in these cell layers leading to enhanced virus spread and severe dysfunction that leads to morbidity. Prophylactic/therapeutic intervention targeting this virus-host interaction may effectively reduce airway and/or gastrointestinal barrier damage and mitigate virus spread.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1

et al. 2021

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“…The opposite case appears in MUPP1-PDZ with HPV [49] and PALS1-PDZ with SARS-CoV-2 [50]; the binding affinity between the viral protein and the PDZ domain is weaker than their respective PDZ-host interactions. Finally, for MAGI1-PDZ interaction with HPV E6, HTLV Tax, AdV E4 ORF1 and two host proteins [51], there is no well-defined trend in affinities differences.…”

Section: Comparison With Other Pdz-ligand Interactions In Bibliographymentioning

confidence: 95%

A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

et al. 2021

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PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. With such an array of relevant and diverse interactions, PDZ binding specificity has been thoroughly studied and a traditional classification has grouped PDZ domains in three major specificity classes. In this work, we have selected four human PDZ domains covering the three canonical specificity-class binding mode and a set of their corresponding binders, including host/natural, viral and designed PDZ motifs. Through calorimetric techniques, we have covered the entire cross interactions between the selected PDZ domains and partners. The results indicate a rather basic specificity in each PDZ domain, with two of the domains that bind their cognate and some non-cognate ligands and the two other domains that basically bind their cognate partners. On the other hand, the host partners mostly bind their corresponding PDZ domain and, interestingly, the viral ligands are able to bind most of the studied PDZ domains, even those not previously described. Some viruses may have evolved to use of the ability of the PDZ fold to bind multiple targets, with resulting affinities for the virus–host interactions that are, in some cases, higher than for host–host interactions.

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“…SPR assay results indicated that the binding affinity of CD147 to S protein was 185 nM. In addition, Cascio et al showed that Short Linear Motifs (SLiMs) of SARS-CoV-2 E protein (E-SLiM) could bind to the PDZ domain of the wild type human PALS1 protein in the micromolar range, which may also help the virus to invade host cells [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Recent progress of surface plasmon resonance in the development of coronavirus disease-2019 drug candidates

Wang

Liu

2021

European Journal of Medicinal Chemistry Reports

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At the end of 2019, the new coronavirus caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly raged, bringing a severe public health crisis to the world. It is urgent to discover suitable drugs and treatment regimens against this coronavirus disease 2019 (COVID-19) and related diseases. Based on the previous knowledge and experience in treating similar diseases, researchers have come up with hundreds of possible drug candidates in the shortest possible time. Based on surface plasmon resonance (SPR) technology, this review summarized the application of SPR technology in COVID-19 research from four aspects: the invasion mode of SARS-CoV-2 into host cells, antibody drug candidates for the treatment of COVID-19, small molecule drug repurposing and vaccines for COVID-19. SPR technology has gradually become a powerful tool to study the interaction between drugs and targets due to its high efficiency, automation, labeling-free and high data resolution. The use of SPR technology can not only obtain the affinity data between drugs and targets, but also clarify the binding sites and mechanisms of drugs. We hope that this review can provide a reference for the subsequent application of SPR technology in antiviral drug development.

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Structural determinants driving the binding process between PDZ domain of wild type human PALS1 protein and SLiM sequences of SARS-CoV E proteins

Abstract: Graphical abstract

Cited by 12 publications

References 50 publications

SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1

SARS-CoV-2 Envelope (E) protein interacts with PDZ-domain-2 of host tight junction protein ZO1

A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

Recent progress of surface plasmon resonance in the development of coronavirus disease-2019 drug candidates

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