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Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

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 Moti...

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Autores principales: Mészáros, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928535/
https://www.ncbi.nlm.nih.gov/pubmed/33436497
http://dx.doi.org/10.1126/scisignal.abd0334
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author Mészáros, 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.
author_facet Mészáros, 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.
author_sort Mészáros, Bálint
collection PubMed
description 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.
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spelling pubmed-79285352021-03-10 Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications Mészáros, 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. Sci Signal Research Resources 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. American Association for the Advancement of Science 2021-01-12 /pmc/articles/PMC7928535/ /pubmed/33436497 http://dx.doi.org/10.1126/scisignal.abd0334 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License (//www.sciencemag.org/about/science-licenses-journal-article-reuse) .
spellingShingle Research Resources
Mészáros, 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.
Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title_full Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title_fullStr Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title_full_unstemmed Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title_short Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
title_sort short linear motif candidates in the cell entry system used by sars-cov-2 and their potential therapeutic implications
topic Research Resources
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928535/
https://www.ncbi.nlm.nih.gov/pubmed/33436497
http://dx.doi.org/10.1126/scisignal.abd0334
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