Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications.
Sci Signal
; 14(665)2021 01 12.
Article
in English
| MEDLINE | ID: covidwho-1029425
ABSTRACT
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 ß3 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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Virus Internalization
/
Host Microbial Interactions
/
SARS-CoV-2
/
COVID-19
Type of study:
Prognostic study
Language:
English
Journal subject:
Science
/
Physiology
Year:
2021
Document Type:
Article
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