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The primary cell surface receptor for SARS-CoV-2 is theangiotensin-converting enzyme 2 (ACE2). Recently it has been noticed that theviral Spike protein has an RGD motif, suggesting that cell surface integrinsmay be co-receptors. We examined the sequences of ACE2 and integrins with theEukaryotic Linear Motif resource, ELM, and were presented with candidate shortlinear motifs (SLiMs) in their short, unstructured, cytosolic tails withpotential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton andcell signalling. These SLiM candidates are highly conserved in vertebrates.They suggest potential interactions with the AP2 mu2 subunit as well as I-BAR,LC3, PDZ, PTB and SH2 domains found in signalling and regulatory proteinspresent in epithelial lung cells. Several motifs overlap in the tail sequences,suggesting that they may act as molecular switches, often involving tyrosinephosphorylation status. Candidate LIR motifs are present in the tails of ACE2and integrin beta3, suggesting that these proteins can directly recruitautophagy components. We also noticed that the extracellular part of ACE2 has aconserved MIDAS structural motif, which are commonly used by beta integrins forligand binding, potentially supporting the proposal that integrins and ACE2share common ligands. The findings presented here identify several molecularlinks and testable hypotheses that might help uncover the mechanisms ofSARS-CoV-2 attachment, entry and replication, and strengthen the possibilitythat it might be possible to develop host-directed therapies to dampen theefficiency of viral entry and hamper disease progression. The strong sequenceconservation means that these putative SLiMs are good candidates: Nevertheless,SLiMs must always be validated by experimentation before they can be stated tobe functional.

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