Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

Kleshchevnikov,; Sandaltzopoulou, Elissavet; Benz, Caroline; Petsalaki, Evangelia

doi:10.1101/2021.06.25.449930

Cited by 5 publications

(4 citation statements)

References 96 publications

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“…SLiMs are disordered, short, linear sequences that contain a limited number of specificity-determining residues ( 55 ). Few mutations are necessary for the generation of new SLiMs, allowing rapid convergent evolution of SLiMs within proteins de novo , enabling rapid functional flexibility ( 56 , 57 ). E. chaffeensis has likely convergently evolved TRP120 SLiMs to engage multiple cellular signaling pathways for redundancy and to influence anti-apoptotic signaling through different pathways.…”

Section: Discussionmentioning

confidence: 99%

Ehrlichia Wnt SLiM ligand mimic deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis

Byerly,

Patterson,

Pittner

et al. 2023

Infect Immun

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Ehrlichia chaffeensis TRP120 effector has evolved short linear motif (SLiM) ligand mimicry to repurpose multiple evolutionarily conserved cellular signaling pathways, including Wnt, Notch, and Hedgehog. In this investigation, we demonstrate that E. chaffeensis and recombinant TRP120 deactivate Hippo signaling, resulting in the activation of Hippo transcription coactivator Yes-associated protein (Yap). Moreover, a homologous 6 amino acid (QDVASH) SLiM shared by TRP120 and Wnt3a/5a ligands phenocopied Yap and β-catenin activation induced by E. chaffeensis, rTRP120, and Wnt5a. Similar Hippo gene expression profiles were also stimulated by E. chaffeensis , rTRP120, SLiM, and Wnt5a. Single siRNA knockdown of Hippo transcription co-activator/factors, Yap, and transcriptional enhanced associate domain (TEAD) significantly decreased E. chaffeensis infection. Yap activation was abolished in THP-1 Wnt Frizzled-5 (Fzd5) receptor knockout cells (KO), demonstrating Fzd5 receptor dependence. In addition, the TRP120-Wnt-SLiM antibody blocked Hippo deactivation (Yap activation). Expression of anti-apoptotic Hippo target gene SLC2A1 (encodes glucose transporter 1; GLUT1) was upregulated by E. chaffeensis and corresponded to increased levels of GLUT1. Conversely, siRNA knockdown of SLC2A1 significantly inhibited infection. Higher GLUT1 levels correlated with increased B cell lymphoma-extra large (BCL-xL) and decreased BCL2-associated X, apoptosis regulator (Bax) levels. Moreover, blocking Yap activation with the inhibitor Verteporfin induced apoptosis that corresponded to significant reductions in GLUT1 and BCL-xL levels and activation of Bax and Caspase-3 and -9. This study identifies a novel shared Wnt/Hippo SLiM ligand mimic and demonstrates that E. chaffeensis deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis.

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Section: Discussionmentioning

confidence: 99%

Ehrlichia Wnt SLiM ligand mimic deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis

Byerly,

Patterson,

Pittner

et al. 2023

Infect Immun

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“…8). Similar secondary structural elements were identified with short protein domains in the dataset that could potentially pose as structural equivalents to short linear motifs (SLiMs) 51 . Outputs of whole and constrained comparisons are available in Supplementary Data 2 and 3.…”

Section: Investigating the Biological Properties Of Sars-cov-2 Spike ...mentioning

confidence: 67%

Identifying and profiling structural similarities between Spike of SARS-CoV-2 and other viral or host proteins with Machaon

Kakoulidis

Vlachos

Thanos

et al. 2022

Preprint

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Using protein structure to predict function, interactions, and evolutionary history is still an open challenge, with existing approaches relying extensively on protein homology and families. Here, we present Machaon, a new data-driven method combining orientation invariant metrics on phi-psi angles, inter-residue contacts and surface complexity. It can be readily applied on whole structures or segments—such as domains and binding sites. Machaon was applied on SARS-CoV-2 Spike monomers of native, Delta and Omicron variants and identified correlations with a wide range of viral proteins from close to distant taxonomy ranks, as well as host receptors, such as ACE2. The associated whole structures have: 32.7% and 38.5% sequence identities on protein secondary structure and gene coding region, 86% chemical and 22.1% protein tertiary structure similarities (median values, native Spike). Machaon’s meta-analysis revealed Spike’s relationships with biological processes such as ubiquitination and angiogenesis and highlighted different patterns in virus attachment among the studied variants. Available at: https://github.com/anastasiadoulab/machaon .

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“…SLiMs drive evolution and rapidly evolve ex nihilo to add new functionality to proteins. Pathogens are known to convergently evolve SLiMs within disordered regions due to the limited number of mutations necessary for the generation of a new SLiM (66). SLiMs contain high evolutionary plasticity due to their disordered nature, short length and limited number of specificity-determining residues (67).…”

Section: Discussionmentioning

confidence: 99%

Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

Byerly

Mitra

Patterson

et al. 2022

Preprint

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Ehrlichia chaffeensis (E. chaffeensis) has evolved eukaryotic ligand mimicry to repurposes multiple cellular signaling pathways for immune evasion. In this investigation, we demonstrate that TRP120 has a novel repetitive short liner motif (SLiM) that activates the evolutionarily conserved Hedgehog (Hh) signaling pathway to inhibit apoptosis. In silico analysis revealed that TRP120 has sequence and functional similarity with Hh ligands and a candidate Hh ligand SLiM was identified. siRNA knockdown of Hh signaling and transcriptional components significantly reduced infection. Co-immunoprecipitation and surface plasmon resonance demonstrated that rTRP120-TR interacted directly with Hh receptor Patched-2 (PTCH2). E. chaffeensis infection resulted in early activation of Hh transcription factor GLI-1 and upregulation of Hh target genes. Moreover, soluble recombinant TRP120 (rTRP120) activated Hh and induced gene expression consistent with the eukaryotic Hh ligand. The TRP120 Hh SLiM (NPEVLIKD) induced nuclear translocation of GLI-1 in THP-1 cells and primary human monocytes and induced a rapid and expansive activation of Hh pathway target genes. Furthermore, Hh activation was blocked by an α-TRP120 Hh SLiM antibody. TRP120 Hh SLiM significantly increased levels of Hh target, anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and siRNA knockdown of BCL-2 dramatically inhibited infection. Blocking Hh signaling with the inhibitor Vismodegib, induced a pro-apoptotic cellular program defined by decreased mitochondria membrane potential, significant reductions in BCL-2, activation of caspase 3 and 9, and increased apoptotic cells. This study reveals a novel E. chaffeensis SLiM ligand mimetic that activates Hh signaling to maintain E. chaffeensis infection by engaging a BCL-2 anti-apoptotic cellular program.

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Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

Cited by 5 publications

References 96 publications

Ehrlichia Wnt SLiM ligand mimic deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis

Ehrlichia Wnt SLiM ligand mimic deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis

Identifying and profiling structural similarities between Spike of SARS-CoV-2 and other viral or host proteins with Machaon

Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

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