A two-layered machine learning method to identify protein O-GlcNAcylation sites with O-GlcNAc transferase substrate motifs

Kao, Hui-Ju; Huang, Chien‐Hsun; Bretaña, Neil Arvin; Lu, Cheng-Tsung; Weng, Shun-Long; Lee, Tzong-Yi

doi:10.1186/1471-2105-16-s18-s10

Cited by 44 publications

(42 citation statements)

References 54 publications

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“…Moreover, the motifs of Ser O-GlcNAcylation and Thr O-GlcNAcylation were surprisingly similar ( Figure 2; supplementary material, Figure S2). This brain O-GlcNAcylation motif feature is consistent with that predicted by the O-GlcNAc prediction programs YinOYang 1.2 server and OGlcNAcScan [33], and predictions based on 410 experimentally verified O-GlcNAcylation sites extracted from dbOGAP, OGlycBase, and UniProtKB [34]. Thus, the O-GlcNAcylation motifs appear to be fairly well conserved across various species and in various organs.…”

Section: Mapping Of O-glcnac In Human Brainsupporting

confidence: 81%

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Wang

Yang

Petyuk

et al. 2017

The Journal of Pathology

107

125

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Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease, however detailed molecular characterization of this important protein posttranslational modification at proteome level has been highly challenging, due to its low stoichiometry and labile nature. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brain tissues with and without Alzheimer’s disease using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty one O-GlcNAc peptides covering 81 proteins were altered in Alzheimer’s brain as compared to controls (q <0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.

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Section: Mapping Of O-glcnac In Human Brainsupporting

confidence: 81%

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Wang

Yang

Petyuk

et al. 2017

The Journal of Pathology

107

125

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“…2A). Interestingly, similar sequence preference has been observed from O-GlcNAcylation sites identified in animals (11,12,24,25), suggesting that the plant and animal OGTs have consistent enzymatic preferences.…”

Section: Enrichment and Identification Of Glcnacylated And Phosphorylmentioning

confidence: 61%

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

Chalkley

Maynard

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

161

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Genetic studies have shown essential functions of O-linked N-acetylglucosamine (O-GlcNAc) modification in plants. However, the proteins and sites subject to this posttranslational modification are largely unknown. Here, we report a large-scale proteomic identification of O-GlcNAc-modified proteins and sites in the model plant Arabidopsis thaliana. Using lectin weak affinity chromatography to enrich modified peptides, followed by mass spectrometry, we identified 971 O-GlcNAc-modified peptides belonging to 262 proteins. The modified proteins are involved in cellular regulatory processes, including transcription, translation, epigenetic gene regulation, and signal transduction. Many proteins have functions in developmental and physiological processes specific to plants, such as hormone responses and flower development. Mass spectrometric analysis of phosphopeptides from the same samples showed that a large number of peptides could be modified by either O-GlcNAcylation or phosphorylation, but cooccurrence of the two modifications in the same peptide molecule was rare. Our study generates a snapshot of the O-GlcNAc modification landscape in plants, indicating functions in many cellular regulation pathways and providing a powerful resource for further dissecting these functions at the molecular level.of proteins consisting of a single O-linked N-acetylglucosamine attached to serine and threonine residues. It has been extensively studied in animals, where it regulates a wide range of developmental and metabolic processes. O-GlcNAcylation is dynamically controlled by two enzymes: an O-GlcNAc transferase (OGT) and an O-GlcNAcase (OGA), which add and remove O-GlcNAc, respectively. O-GlcNAcylation occurs in the cytoplasm, nucleus, and mitochondria and has been implicated in cellular processes, including transcription, translation, signal transduction, nuclear pore function, epigenetic regulation and proteasomal degradation (1). Altered levels of protein O-GlcNAcylation in animals have been associated with neurodegeneration, diabetes, cardiovascular diseases, and cancer (2) whereas knock out of OGT is embryonically lethal (3).The model plant Arabidopsis has two putative OGTs: SPINDLY (SPY) and SECRET AGENT (SEC). The spy mutant was identified based on its phenotypes that mimic gibberellin-treated plants, with elongated stems (4). The spy plants also show defects in light and cytokinin responses, leaf morphology and phyllotaxy, root growth, meristem activity, and circadian rhythms (5). The sec mutant displays defects in flower development (6). Although OGT enzymatic activity has been demonstrated in SEC, similar activity in SPY has not been confirmed (7). However, the spy;sec double mutants show severe defects in the development of gametes and are embryonically lethal (7), similar to the OGT knockout mutant in animals. Thus, genetic evidence indicates that O-GlcNAc modification is as important in plants as in animals. But little is known about its specific functions because few O-GlcNAc-modified proteins have been identified...

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“…O-β-GlcNAc modification potential sites were predicted by using YinOYang 1.2 (http://www.cbs.dtu.dk/services/YingOYang/) (Gupta and Brunak, 2002), OGTSITE (http://csb.cse.yzu.edu.tw/OGTSite/index.php) (Kao et al, 2015) and GlycoEP (http://crdd.osdd.net/raghava/glycoep/) (Chauhan et al, 2013).…”

Section: Prediction Of O-β-glcnacylated Residuesmentioning

confidence: 99%

O-β-GlcNAcylation, Chloroquine and 2-Hydroxybenzohydrazine May Hamper SARS-CoV-2 entry to Human via Inhibition of ACE2 Phosphorylation at Ser787 but Also Induce Disruption of Virus-ACE2 Binding

Ahmad¹,

Shabbiri²,

Islam³

2020

Preprint

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The novel coronavirus COVID-19 disease is extremely contagious and has been spread worldwide. First COVID-19 case was identified in December, 2019 and within three months, more than one million affected cases and over 65,000 deaths have been reported. SARS-coronavirus 2 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 22 April 2020 to the SARS CoV (Severe Acute Respiratory Syndrome corona virus) family. The SARS-CoV-2 enters the human body by binding its viral surface spike protein with the host angiotensinconverting enzyme 2 (ACE2) receptors and cause infection. To prevent the virus entry and its transmission in the human body, we focused on the two domains of ACE2: i) the N-terminal extracellular binding domain (18-740 residues) reported for coronavirus spike interaction, and ii) the C-terminal cytoplasmic region (762-805 residues) to prevent the virus transmission. Therefore, we proposed: i) inhibition of receptor binding domain (RBD) of SARS-CoV-2 and human ACE2 protein may prevent the virus entry to the host and ii) inhibition of phosphorylation at Ser-787 of ACE2 protein may prevent the transmission of the virus in the COVID-19 patients. In the past, the critical role of Ser 787 in human ACE2 protein has been experimentally verified in SARS-CoV transmission, that upon binding to the receptor, SARS-CoV induces CKII-mediated phosphorylation of ACE2 at Ser-787 that in-turn facilitate virus entry to host cells, followed by replication and activation of ACE2, initiates downstream signaling leading to lung fibrosis. Therefore, in this study, we have suggested post-translational modification (PTM) O-β-GlcNAcylation, and two compounds Chloroquine and 2-hydroxybenzohydrazine might share the common pathways to prevent the COVID-19 infection in human. The addition of O-β-GlcNAcylation at same or neighboring Ser/ Thr residues results in phosphorylation inhibition and a change in protein structural and functional confirmations. Thereby, using neural networking methods, we have identified Ser/ Thr residues in ACE2 that are potential sites for phosphorylation and / or O-β-GlcNAcylation. Molecular docking showed that UDP-GlcNAc has more binding affinity with Ser-787 than the phosphoryl group. Moreover, chloroquine and 2hydroxybenzohydrazine also showed great potential to bind at Ser-787 that may result in inhibition of Ser-787 phosphorylation and downstream signaling. Furthermore, O-β-GlcNAcylation, chloroquine and 2-hydroxybenzohydrazine showed their high affinity at ACE2-SARS-CoV-2receptor binding domain that may prevent the entry of SARS-CoV-2 into human body. In conclusion, inhibition of human ACE2 phosphorylation at Ser-787 and ACE2-SARS-CoV-2 binding domain could be promising targets against SARS-CoV-2 infection.

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A two-layered machine learning method to identify protein O-GlcNAcylation sites with O-GlcNAc transferase substrate motifs

Cited by 44 publications

References 54 publications

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

<strong>O-β-GlcNAcylation,</strong><strong> Chloroquine and </strong><strong>2-Hydroxybenzohydrazine May Hamper SARS-CoV-2 entry to Human via Inhibition of ACE2 Phosphorylation at Ser787 but Also Induce Disruption of Virus-ACE2 Binding</strong>

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A two-layered machine learning method to identify protein O-GlcNAcylation sites with O-GlcNAc transferase substrate motifs

Cited by 44 publications

References 54 publications

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Quantitative proteomics identifies altered O‐GlcNAcylation of structural, synaptic and memory‐associated proteins in Alzheimer's disease

Proteomic analysis reveals O-GlcNAc modification on proteins with key regulatory functions in Arabidopsis

<strong>O-&beta;-GlcNAcylation,</strong><strong> Chloroquine and </strong><strong>2-Hydroxybenzohydrazine May Hamper SARS-CoV-2 entry to Human via Inhibition of ACE2 Phosphorylation at Ser787 but Also Induce Disruption of Virus-ACE2 Binding</strong>

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<strong>O-β-GlcNAcylation,</strong><strong> Chloroquine and </strong><strong>2-Hydroxybenzohydrazine May Hamper SARS-CoV-2 entry to Human via Inhibition of ACE2 Phosphorylation at Ser787 but Also Induce Disruption of Virus-ACE2 Binding</strong>