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description Publicationkeyboard_double_arrow_right Article 2021 ArgentinaPublisher:American Association for the Advancement of Science (AAAS) Funded by:EC | MIMIC, EC | PDZnet, UKRI | Thirdfort - Data driven p... +1 projectsEC| MIMIC ,EC| PDZnet ,UKRI| Thirdfort - Data driven property fraud prevention ,EC| IDPfunAuthors: Mészáros, Bálint; Sámano-Sánchez, Hugo; Alvarado-Valverde, Jesús; Čalyševa, Jelena; +7 AuthorsMészáros, Bálint; Sámano-Sánchez, Hugo; Alvarado-Valverde, Jesús; Čalyševa, Jelena; Martínez-Pérez, Elizabeth; Alves, Renato; Shields, Denis C.; Kumar, Manjeet; Rippmann, Friedrich; Chemes, Lucía B.; Gibson, Toby J.;The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions. SARS-CoV-2: From entry to autophagy? SARS-CoV-2, the virus that causes COVID-19, enters cells through endocytosis upon binding to the cell surface receptor ACE2 and potentially others, including integrins. Using bioinformatics, Mészáros et al. predicted the presence of short amino acid sequences, called short linear motifs (SLiMs), in the cytoplasmic tails of ACE2 and various integrins that may engage the endocytic and autophagic machinery. Using affinity binding assays, Kliche et al. not only confirmed that many of these predicted SLiMs interacted with target peptides in various components of the endocytosis and autophagy machinery but also found that these interactions were regulated by the phosphorylation of SLiM-adjacent amino acids. Together, these findings have identified a potential link between autophagy and integrin signaling and could lead to new ways to prevent viral infection. Cytosolic tail motifs in host cell surface receptors predict modes of SARS-CoV-2 entry and propagation.
Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2021Full-Text: http://europepmc.org/articles/PMC7928535Data sources: PubMed CentralCONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y TécnicasArticle . 2021License: CC BY NC SAScience SignalingOther literature type . Article . 2021 . Peer-reviewedarXiv.org e-Print ArchiveOther literature type . Preprint . 2020Data sources: arXiv.org e-Print Archiveadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
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For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 57 citations 57 popularity Top 1% influence Average impulse Top 1% Powered by BIP!more_vert Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2021Full-Text: http://europepmc.org/articles/PMC7928535Data sources: PubMed CentralCONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y TécnicasArticle . 2021License: CC BY NC SAScience SignalingOther literature type . Article . 2021 . Peer-reviewedarXiv.org e-Print ArchiveOther literature type . Preprint . 2020Data sources: arXiv.org e-Print Archiveadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
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description Publicationkeyboard_double_arrow_right Article 2021 ArgentinaPublisher:American Association for the Advancement of Science (AAAS) Funded by:EC | MIMIC, EC | PDZnet, UKRI | Thirdfort - Data driven p... +1 projectsEC| MIMIC ,EC| PDZnet ,UKRI| Thirdfort - Data driven property fraud prevention ,EC| IDPfunAuthors: Mészáros, Bálint; Sámano-Sánchez, Hugo; Alvarado-Valverde, Jesús; Čalyševa, Jelena; +7 AuthorsMészáros, Bálint; Sámano-Sánchez, Hugo; Alvarado-Valverde, Jesús; Čalyševa, Jelena; Martínez-Pérez, Elizabeth; Alves, Renato; Shields, Denis C.; Kumar, Manjeet; Rippmann, Friedrich; Chemes, Lucía B.; Gibson, Toby J.;The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions. SARS-CoV-2: From entry to autophagy? SARS-CoV-2, the virus that causes COVID-19, enters cells through endocytosis upon binding to the cell surface receptor ACE2 and potentially others, including integrins. Using bioinformatics, Mészáros et al. predicted the presence of short amino acid sequences, called short linear motifs (SLiMs), in the cytoplasmic tails of ACE2 and various integrins that may engage the endocytic and autophagic machinery. Using affinity binding assays, Kliche et al. not only confirmed that many of these predicted SLiMs interacted with target peptides in various components of the endocytosis and autophagy machinery but also found that these interactions were regulated by the phosphorylation of SLiM-adjacent amino acids. Together, these findings have identified a potential link between autophagy and integrin signaling and could lead to new ways to prevent viral infection. Cytosolic tail motifs in host cell surface receptors predict modes of SARS-CoV-2 entry and propagation.
Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2021Full-Text: http://europepmc.org/articles/PMC7928535Data sources: PubMed CentralCONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y TécnicasArticle . 2021License: CC BY NC SAScience SignalingOther literature type . Article . 2021 . Peer-reviewedarXiv.org e-Print ArchiveOther literature type . Preprint . 2020Data sources: arXiv.org e-Print Archiveadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1126/scisignal.abd0334&type=result"></script>'); --> </script>
For further information contact us at helpdesk@openaire.euAccess RoutesGreen bronze 57 citations 57 popularity Top 1% influence Average impulse Top 1% Powered by BIP!more_vert Europe PubMed Centra... arrow_drop_down Europe PubMed CentralArticle . 2021Full-Text: http://europepmc.org/articles/PMC7928535Data sources: PubMed CentralCONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y TécnicasArticle . 2021License: CC BY NC SAScience SignalingOther literature type . Article . 2021 . Peer-reviewedarXiv.org e-Print ArchiveOther literature type . Preprint . 2020Data sources: arXiv.org e-Print Archiveadd ClaimPlease grant OpenAIRE to access and update your ORCID works.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.This Research product is the result of merged Research products in OpenAIRE.
You have already added works in your ORCID record related to the merged Research product.All Research productsarrow_drop_down <script type="text/javascript"> <!-- document.write('<div id="oa_widget"></div>'); document.write('<script type="text/javascript" src="https://www.openaire.eu/index.php?option=com_openaire&view=widget&format=raw&projectId=10.1126/scisignal.abd0334&type=result"></script>'); --> </script>
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