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

Autores
Mészáros, Bálint; Sámano Sánchez, Hugo; Alvarado Valverde, Jesús; Čalyševa, Jelena; Martinez Perez, Elizabeth; Alves, Renato; Shields, Denis C.; Kumar, Manjeet; Rippmann, Friedrich; Chemes, Lucia Beatriz; Gibson, Toby James
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Mészáros, Bálint. European Molecular Biology Laboratory; Alemania
Fil: Sámano Sánchez, Hugo. European Molecular Biology Laboratory; Alemania
Fil: Alvarado Valverde, Jesús. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; Alemania
Fil: Čalyševa, Jelena. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; Alemania
Fil: Martinez Perez, Elizabeth. Fundación Instituto Leloir; Argentina. European Molecular Biology Laboratory; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alves, Renato. European Molecular Biology Laboratory; Alemania
Fil: Shields, Denis C.. Universidad de Dublin; Irlanda
Fil: Kumar, Manjeet. European Molecular Biology Laboratory; Alemania
Fil: Rippmann, Friedrich. Computational Chemistry & Biology; Alemania
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Gibson, Toby James. European Molecular Biology Laboratory; Alemania
Materia
COVID-19
ACE2
INTEGRINS
SPIKE
SLIMS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/135517
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/135517
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implicationsMészáros, BálintSámano Sánchez, HugoAlvarado Valverde, JesúsČalyševa, JelenaMartinez Perez, ElizabethAlves, RenatoShields, Denis C.Kumar, ManjeetRippmann, FriedrichChemes, Lucia BeatrizGibson, Toby JamesCOVID-19ACE2INTEGRINSSPIKESLIMShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3The 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.Fil: Mészáros, Bálint. European Molecular Biology Laboratory; AlemaniaFil: Sámano Sánchez, Hugo. European Molecular Biology Laboratory; AlemaniaFil: Alvarado Valverde, Jesús. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Čalyševa, Jelena. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Martinez Perez, Elizabeth. Fundación Instituto Leloir; Argentina. European Molecular Biology Laboratory; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alves, Renato. European Molecular Biology Laboratory; AlemaniaFil: Shields, Denis C.. Universidad de Dublin; IrlandaFil: Kumar, Manjeet. European Molecular Biology Laboratory; AlemaniaFil: Rippmann, Friedrich. Computational Chemistry & Biology; AlemaniaFil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Gibson, Toby James. European Molecular Biology Laboratory; AlemaniaAmerican Association for the Advancement of Science2021-01-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/135517Mészáros, Bálint; Sámano Sánchez, Hugo; Alvarado Valverde, Jesús; Čalyševa, Jelena; Martinez Perez, Elizabeth; et al.; Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications; American Association for the Advancement of Science; Science Signaling; 14; 665; 12-1-2021; 1-261945-08771937-9145CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1126/SCISIGNAL.ABD0334info:eu-repo/semantics/altIdentifier/url/https://stke.sciencemag.org/content/14/665/eabd0334info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:16:29Zoai:ri.conicet.gov.ar:11336/135517instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:16:29.784CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 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
spellingShingle Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
Mészáros, Bálint
COVID-19
ACE2
INTEGRINS
SPIKE
SLIMS
title_short 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_sort Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
dc.creator.none.fl_str_mv Mészáros, Bálint
Sámano Sánchez, Hugo
Alvarado Valverde, Jesús
Čalyševa, Jelena
Martinez Perez, Elizabeth
Alves, Renato
Shields, Denis C.
Kumar, Manjeet
Rippmann, Friedrich
Chemes, Lucia Beatriz
Gibson, Toby James
author Mészáros, Bálint
author_facet Mészáros, Bálint
Sámano Sánchez, Hugo
Alvarado Valverde, Jesús
Čalyševa, Jelena
Martinez Perez, Elizabeth
Alves, Renato
Shields, Denis C.
Kumar, Manjeet
Rippmann, Friedrich
Chemes, Lucia Beatriz
Gibson, Toby James
author_role author
author2 Sámano Sánchez, Hugo
Alvarado Valverde, Jesús
Čalyševa, Jelena
Martinez Perez, Elizabeth
Alves, Renato
Shields, Denis C.
Kumar, Manjeet
Rippmann, Friedrich
Chemes, Lucia Beatriz
Gibson, Toby James
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COVID-19
ACE2
INTEGRINS
SPIKE
SLIMS
topic COVID-19
ACE2
INTEGRINS
SPIKE
SLIMS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Mészáros, Bálint. European Molecular Biology Laboratory; Alemania
Fil: Sámano Sánchez, Hugo. European Molecular Biology Laboratory; Alemania
Fil: Alvarado Valverde, Jesús. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; Alemania
Fil: Čalyševa, Jelena. European Molecular Biology Laboratory; Alemania. Ruprecht Karls Universitat Heidelberg; Alemania
Fil: Martinez Perez, Elizabeth. Fundación Instituto Leloir; Argentina. European Molecular Biology Laboratory; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alves, Renato. European Molecular Biology Laboratory; Alemania
Fil: Shields, Denis C.. Universidad de Dublin; Irlanda
Fil: Kumar, Manjeet. European Molecular Biology Laboratory; Alemania
Fil: Rippmann, Friedrich. Computational Chemistry & Biology; Alemania
Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Gibson, Toby James. European Molecular Biology Laboratory; Alemania
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.
publishDate 2021
dc.date.none.fl_str_mv 2021-01-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/135517
Mészáros, Bálint; Sámano Sánchez, Hugo; Alvarado Valverde, Jesús; Čalyševa, Jelena; Martinez Perez, Elizabeth; et al.; Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications; American Association for the Advancement of Science; Science Signaling; 14; 665; 12-1-2021; 1-26
1945-0877
1937-9145
CONICET Digital
CONICET
url http://hdl.handle.net/11336/135517
identifier_str_mv Mészáros, Bálint; Sámano Sánchez, Hugo; Alvarado Valverde, Jesús; Čalyševa, Jelena; Martinez Perez, Elizabeth; et al.; Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications; American Association for the Advancement of Science; Science Signaling; 14; 665; 12-1-2021; 1-26
1945-0877
1937-9145
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1126/SCISIGNAL.ABD0334
info:eu-repo/semantics/altIdentifier/url/https://stke.sciencemag.org/content/14/665/eabd0334
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for the Advancement of Science
publisher.none.fl_str_mv American Association for the Advancement of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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