Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
Meszaros, B., Samano-Sanchez, H., Alvarado-Valverde, J., Calyseva, J., Martinez-Perez, E., Alves, R., Shields, D. C., Kumar, M., Rippmann, F., Chemes, L. B. and Gibson, T. J.
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany. balint.meszaros@embl.de manjeet.kumar@embl.de lchemes@iib.unsam.edu.ar toby.gibson@embl.de.
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences.
Laboratorio de bioinformatica estructural, Fundacion Instituto Leloir, C1405BWE Buenos Aires, Argentina.
School of Medicine, University College Dublin, Dublin 4, Ireland.
Computational Chemistry & Biology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Instituto de Investigaciones Biotecnologicas "Dr. Rodolfo A. Ugalde", IIB-UNSAM, IIBIO-CONICET, Universidad Nacional de San Martin, CP1650 San Martin, Buenos Aires, Argentina. balint.meszaros@embl.de manjeet.kumar@embl.de lchemes@iib.unsam.edu.ar toby.gibson@embl.de.
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.
Science Signaling. 14(665): en prensa (2021)