Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain

Javorsky, Airah; Humbert, Patrick O.; Kvansakul, Marc

doi:10.1038/s42003-021-02250-7

Cited by 48 publications

(55 citation statements)

References 45 publications

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“…SARS-2 proteins encode both ITAM and ITIM motifs. SARS-2 proteins harbor multiple domain-interacting motifs, such as motifs recognizing PDZ, SH2, SH3 domains [29][30][31]33], Figure 3B. These motifs are essential for cellular signaling and protein trafficking within host cells.…”

Section: The Potential Cov-human Protein Interactions Pathways Based On Functional Motifmentioning

confidence: 99%

“…These motifs are essential for cellular signaling and protein trafficking within host cells. For example, the PDZ-binding and DLLV motifs in SARS-1 E protein can influence the subcellular localization of PALS1 (MPP5), which may disrupt the tight junction and apicobasal polarity of the cell [30,31,34], Figure 3B. The L-rich and PDZ-binding motifs are used by multiple viruses to recruits mTORC1, kinase signaling to initiate translation [7].…”

Section: The Potential Cov-human Protein Interactions Pathways Based On Functional Motifmentioning

confidence: 99%

“…(E) The sequence logo and consensus sequences of nsp1 C-terminus of coronaviruses. The figures(A-C) adopted from[28][29][30][31][32]; (D-E) from EBI portal (https://www.ebi.ac.uk/thornton-srv/ databases/cgi-bin/VarSite/GetPage.pl?home=TRUE, last accessed on 30 August 2021, UniProt ID: P0DTD1_1).…”

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confidence: 99%

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The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

Sobhy

2021

COVID

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Coronaviruses (CoVs) are a large viral family that can evolve rapidly emerging new strains that cause outbreaks and life-loss, including SARS-CoV, MERS-CoV, and SARS-CoV-2 (COVID-19). CoVs encode a diverse number of proteins, ranging from 5 proteins in bat CoV, to 14 in SARS CoV, which could have implication on viral tropism and pathogenicity. Here, we highlight the functional protein motifs (domains) that could contribute in the coronavirus infection and severity, including SARS-CoV-2. For this role, we used the experimentally validated domain (motif) datasets that are known to be crucial for viral infection. Then, we highlight the potential molecular pathways and interactions of SARS-CoV-2 proteins within human cells. Interestingly, the C-terminal of SARS-COV-2 nsp1 protein encodes MREL motif, which a signature motif of the tubulin superfamily, and regulate tubulin expression. The C-terminal region of nsp1 protein can bind to ribosome and regulation viral RNA translation.

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Section: The Potential Cov-human Protein Interactions Pathways Based On Functional Motifmentioning

confidence: 99%

Section: The Potential Cov-human Protein Interactions Pathways Based On Functional Motifmentioning

confidence: 99%

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The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

Sobhy

2021

COVID

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“…As above-mentioned, the PDZ interaction between viral E protein and host PALS1 [46,47] or ZO-1 [23] could demolish cell tight junctions and, consequently, interfere with intercellular signaling and communication. Accordingly, the neighboring cells will lose the direct exchange of metabolites and signaling molecules such as extracellular messengers and hormones required for ensuing intracellular signaling transduction, as in the case of the functional definition of ATP and serotonin in paracrine signaling [48].…”

Section: Possible Damaged Gpcr Signaling By Sars-cov-2 Invasionmentioning

confidence: 99%

Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications

Zhang

Friedman

2021

IJMS

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SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial barrier. Conversely, receptor-mediated viral invasion ensures limited but targeted infections in multiple organs. The ACE2 receptor represents the major virion loading site by virtue of its wide tissue distribution as demonstrated in highly susceptible lung, intestine, and kidney. In brain, NRP1 mediates viral endocytosis in a similar manner to ACE2. Prominently, PDZ interaction involves the entire viral loading process either outside or inside the host cells, whereas E, ACE2, and NRP1 provide the PDZ binding motif required for interacting with PDZ domain-containing proteins PALS1, ZO-1, and NHERF1, respectively. Hijacking NHERF1 and β-arrestin by virion loading may impair specific sensory GPCR signalosome assembling and cause disordered cellular responses such as loss of smell and taste. PDZ interaction enhances SARS-CoV-2 invasion by supporting viral receptor membrane residence, implying that the disruption of these interactions could diminish SARS-CoV-2 infections and be another therapeutic strategy against COVID-19 along with antibody therapy. GPCR-targeted drugs are likely to alleviate pathogenic symptoms-associated with SARS-CoV-2 infection.

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“…The best studied examples include 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 motif at its C-terminus (sequence: DVQ T S F , motif residues are underlined) and is also regulated by PDZ domains [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Choanoflagellates are single-celled eukaryotes with complex signaling pathways. They are considered the closest non-metazoan ancestors to mammals and other metazoans and form multicellular-like states called rosettes. The choanoflagellate Monosiga brevicollis contains over 150 PDZ domains, an important peptide-binding domain in all three domains of life (Archaea, Bacteria, and Eukarya). Therefore, an understanding of PDZ domain signaling pathways in choanoflagellates may provide insight into the origins of multicellularity. PDZ domains recognize the C-terminus of target proteins and regulate signaling and trafficking pathways, as well as cellular adhesion. Here, we developed a computational software suite, Domain Analysis and Motif Matcher (DAMM), that analyzes peptide-binding cleft sequence identity as compared with human PDZ domains and that can be used in combination with literature searches of known human PDZ-interacting sequences to predict target specificity in choanoflagellate PDZ domains. We used this program, protein biochemistry, fluorescence polarization, and structural analyses to characterize the specificity of A9UPE9_MONBE, a M. brevicollis PDZ domain-containing protein with no homology to any metazoan protein, finding that its PDZ domain is most similar to those of the DLG family. We then identified two endogenous sequences that bind A9UPE9 PDZ with <100 μM affinity, a value commonly considered the threshold for cellular PDZ–peptide interactions. Taken together, this approach can be used to predict cellular targets of previously uncharacterized PDZ domains in choanoflagellates and other organisms. Our data contribute to investigations into choanoflagellate signaling and how it informs metazoan evolution.

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Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain

Cited by 48 publications

References 45 publications

The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

The Potential Functions of Protein Domains during COVID Infection: An Analysis and a Review

Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications

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

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