Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Kliche, Johanna; Ali, Muhammad; Ivarsson, Ylva

doi:10.1101/2020.10.06.327742

Cited by 13 publications

(27 citation statements)

References 64 publications

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“…S3) indicates that this motif instance has an even earlier evolutionary origin than the origin of ACE2 itself, hinting at a key role in internalization. As expected, because the specificity is not yet defined, Dab1 and four other tested PTB domains did not bind to the ACE2 tail region (48). A poorly soluble sorting nexin 17 (SNX17) FERM domain was found to bind with ≈100 M affinity, providing an ambiguous result.…”

Section: Proteinmentioning

confidence: 66%

“…Thus, the mammalian ACE2, which internalizes the coronavirus, has a SLiM candidate for internalization appropriately located within its cytosolic tail. The ACE2 tail sequence was found to bind with moderate affinity to AP2 μ2 subunit ( 48 ) well within the 30 to 100 μM range of biologically relevant affinities.…”

Section: Resultsmentioning

confidence: 99%

“…While the YxxPhi, NPY, and LIR motifs require an unphosphorylated state of Tyr 781 , the SH2 motif requires Tyr 781 phosphorylation, creating the opportunity for a multiway phospho-switch acting in this region of ACE2 that directs different steps of the SARS-CoV-2 infection cycle. In support of this proposal, Kliche et al (48) confirmed that the ACE2-YxxPhi interaction is negatively regulated by phosphorylation and that binding to the FYN SH2 domain requires Tyr 781 phos-phorylation. The relative affinities of the ACE2 tail binders, which is still to be fully established, will dictate the competition between the interactions and the functional output.…”

Section: Tyr 781 In the Ace2 Tail Creates A Potential Multiway Molecumentioning

confidence: 85%

“…We first focus on the extracellular SLiMs, before moving across the membrane to examine the cytosolic potential of the receptor tails. In a coincidently published paper, experimental testing of several motifs in the receptor tails is presented ( 48 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Proteinmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Tyr 781 In the Ace2 Tail Creates A Potential Multiway Molecumentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

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“…They found conserved motifs on the cytoplasmatic tails of ACE2 and integrin β3 that interacts with several critical regulatory protein domains. This motif information was tested later on experimental binding affinity measurements [ 19 ] and found that NHERF3 PDZ1, SHANK1 and SNX27 PDZ domains bind to synthetic peptides of the ACE2, and to the synthetic ATG8 domains, MAP1LC3s and GABARAPs, of integrin β3. Those studies exemplify the utility of motif predictions to guide experimental proposals.…”

Section: Introductionmentioning

confidence: 99%

The analysis on the human protein domain targets and host-like interacting motifs for the MERS-CoV and SARS-CoV/CoV-2 infers the molecular mimicry of coronavirus

et al. 2021

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The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses’ proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.

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Marine sulfated polysaccharides as potential antiviral drug candidates to treat Corona Virus disease (COVID-19)

Andrew

Jayaraman

2021

Carbohydrate Research

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The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection.

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Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Cited by 13 publications

References 64 publications

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

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

The analysis on the human protein domain targets and host-like interacting motifs for the MERS-CoV and SARS-CoV/CoV-2 infers the molecular mimicry of coronavirus

Marine sulfated polysaccharides as potential antiviral drug candidates to treat Corona Virus disease (COVID-19)

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