Comparing the binding properties of peptides mimicking the Envelope protein of <scp>SARS‐CoV</scp> and <scp>SARS‐CoV</scp>‐2 to the <scp>PDZ</scp> domain of the tight junction‐associated <scp>PALS1</scp> protein

Toto, Angelo; Ma, Sana; Malagrinò, Francesca; Visconti, Lorenzo; Pagano, Livia; Strømgaard, Kristian; Gianni, Stefano

doi:10.1002/pro.3936

Cited by 50 publications

(54 citation statements)

References 18 publications

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“…1 , Supplementary Data 1 ). It is to be noted here, aa variations in this domain, particularly Ser 55 -Phe 56 and Arg 69 predicted to improve the interaction of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 than SARS-CoV ( De Maio et al, 2020 ; Toto et al, 2020 ). Furthermore, aa at C-terminal end (DLLV: 72–75) directly interact with the PALS1 protein.…”

Section: The Studymentioning

confidence: 61%

“…However, C-terminal domain of monomeric E protein affects the host's intracellular activities through interference with the endoplasmic reticulum, Golgi and the ER-Golgi intermediate compartment ( Li et al, 2014 ). Interaction between the C-terminal domain binding motif (DLLV) of SARS Envelope and PALS1 disrupt tight junctions of epithelial cells promoting virus spread and thus play a key role in the SARS-CoV pathology and suspected to affect the integrity of the lung epithelia ( De Maio et al, 2020 ; Toto et al, 2020 ).…”

Section: The Studymentioning

confidence: 99%

“…Furthermore, aa at C-terminal end (DLLV: 72–75) directly interact with the PALS1 protein. More frequent aa variations with altered polarity of the side chains at these sites could play a critical role in COVID-19 pathogenesis leading to increased epithelial cell disruption and promoted virus spread ( Table 1 , Supplementary Data 1 ) ( De Maio et al, 2020 ; Toto et al, 2020 ).…”

Section: The Studymentioning

confidence: 99%

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Mutational insights into the envelope protein of SARS-CoV-2

et al. 2021

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The ongoing mutations in the structural proteins of SARS-CoV-2 are the major impediment for prevention and control of the COVID-19 disease. Presently we focused on evolution of the envelope (E) protein, one of the most enigmatic and less studied protein among the four structural proteins (S, E, M and N) associated with multitude of immunopathological functions of SARS-CoV-2. In the present study, we comprehensively analyzed 81,818 high quality E protein sequences of SARS-CoV-2 globally available in the GISAID database as of 20 August 2020. Compared to Wuhan reference strain, our mutational analysis explored only 1.2 % (982/81818) mutant strains undergoing a total of 115 unique amino acid (aa) substitutions in the E protein, highlighting the fact that most (98.8 %) of the E protein of SARS-CoV-2 strains are highly conserved. Moreover, we found 58.77 % (134 of 228) nucleotides (nt) positions of SARS-CoV-2 E gene encountering a total of 176 unique nt-level mutations globally, which may affect the efficacy of real time RT-PCR-based molecular detection of COVID-19. Importantly, higher aa variations observed in the C-terminal domain (CTD) of the E protein, particularly at Ser 55 -Phe 56 , Arg 69 and the C-terminal end (DLLV: 72–75) may alter the binding of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 and thus could play a key role in COVID-19 pathogenesis. Furthermore, this study revealed the V25A mutation in the transmembrane domain which is a key factor for the homopentameric conformation of E protein. Our analysis also observed a triple cysteine motif harboring mutation (L39M, A41S, A41V, C43F, C43R, C43S, C44Y, N45R) which may hinder the binding of E protein with spike glycoprotein. These results therefore suggest the continuous monitoring of the structural proteins including the envelope protein of SARS-CoV-2 since the number of genome sequences from across the world are continuously increasing.

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Section: The Studymentioning

confidence: 61%

Section: The Studymentioning

confidence: 99%

Section: The Studymentioning

confidence: 99%

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Mutational insights into the envelope protein of SARS-CoV-2

et al. 2021

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“…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. In a subsequent study, the C-terminal sequences of SARS-CoV-2 E protein were also predicted to bind to the PDZ domain of PALS1 [14, 15]. We did not detect an E-PALS1 interaction, since the PDZ domain of PALS1 was not included in the screening array (Fig 2).…”

Section: Discussionmentioning

confidence: 94%

“…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 PDZ-domain bearing proteins via this putative PBM. Indeed, recent studies showed that the SARS-CoV-2 E protein exhibited an increased affinity for PALS1 [9, 15].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Envelope (E) Protein Interacts with PDZ-Domain-2 of Host Tight Junction Protein ZO1

Shepley-McTaggart

Sagum

Oliva

et al. 2020

Preprint

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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 respiratory dysfunction that leads to morbidity. Prophylactic/therapeutic intervention targeting this virus-host interaction may effectively reduce airway barrier damage and mitigate virus spread.

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Comparing the binding properties of peptides mimicking the Envelope protein of SARS‐CoV and SARS‐CoV‐2 to the PDZ domain of the tight junction‐associated PALS1 protein

Toto

Malagrinò

et al. 2020

Protein Science

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The Envelope protein (E) is one of the four structural proteins encoded by the genome of SARS-CoV and SARS-CoV-2 Coronaviruses. It is an integral membrane protein, highly expressed in the host cell, which is known to have an important role in Coronaviruses maturation, assembly and virulence. The E protein presents a PDZ-binding motif at its C-terminus. One of the key interactors of the E protein in the intracellular environment is the PDZ containing protein PALS1. This interaction is known to play a key role in the SARS-CoV pathology and suspected to affect the integrity of the lung epithelia. In this paper we measured and compared the affinity of peptides mimicking the E protein from SARS-CoV and SARS-CoV-2 for the PDZ domain of PALS1, through equilibrium and kinetic binding experiments. Our results support the hypothesis that the increased virulence of SARS-CoV-2 compared to SARS-CoV may rely on the increased affinity of its Envelope protein for PALS1.

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Comparing the binding properties of peptides mimicking the Envelope protein of SARS‐CoV and SARS‐CoV‐2 to the PDZ domain of the tight junction‐associated PALS1 protein

Cited by 50 publications

References 18 publications

Mutational insights into the envelope protein of SARS-CoV-2

Mutational insights into the envelope protein of SARS-CoV-2

SARS-CoV-2 Envelope (E) Protein Interacts with PDZ-Domain-2 of Host Tight Junction Protein ZO1

Comparing the binding properties of peptides mimicking the Envelope protein of SARS‐CoV and SARS‐CoV‐2 to the PDZ domain of the tight junction‐associated PALS1 protein

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