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HYPE mediated AMPylation profiling in human lysates

ABSTRACT: We describe here the first example of global chemoproteomic screening and substrate validation for HYPE mediated AMPylation in mammalian cell lysate. Through quantitative mass spectrometry-based proteomics coupled with novel chemoproteomic tools providing MS/MS evidence of AMP modification we identified a total of 27 AMPylated proteins, including the previously validated substrate, ER chaperone BiP (HSPA5), along with novel substrates involved in pathways of gene expression, ATP biosynthesis and maintenance of cytoskeleton. This dataset represents the largest library of AMPylated human proteins reported to date and a foundation for substrate-specific investigations that can ultimately decipher the complex biological networks involved in eukaryotic AMPylation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Edward W. Tate

PROVIDER: MSV000080782 | MassIVE | Wed Mar 29 14:01:00 BST 2017

SECONDARY ACCESSION(S): PXD002601

REPOSITORIES: MassIVE

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Global Profiling of Huntingtin-associated protein E (HYPE)-Mediated AMPylation through a Chemical Proteomic Approach.

Broncel Malgorzata M Serwa Remigiusz A RA Bunney Tom D TD Katan Matilda M Tate Edward W EW

Molecular & cellular proteomics : MCP 20151124 2

AMPylation of mammalian small GTPases by bacterial virulence factors can be a key step in bacterial infection of host cells, and constitutes a potential drug target. This posttranslational modification also exists in eukaryotes, and AMP transferase activity was recently assigned to HYPE Filamentation induced by cyclic AMP domain containing protein (FICD) protein, which is conserved from Caenorhabditis elegans to humans. In contrast to bacterial AMP transferases, only a small number of HYPE subst ...[more]

PMID: 26604261

Similar Datasets

HYPE mediated AMPylation profiling in human lysates

Project description:We describe here the first example of global chemoproteomic screening and substrate validation for HYPE mediated AMPylation in mammalian cell lysate. Through quantitative mass spectrometry-based proteomics coupled with novel chemoproteomic tools providing MS/MS evidence of AMP modification we identified a total of 27 AMPylated proteins, including the previously validated substrate, ER chaperone BiP (HSPA5), along with novel substrates involved in pathways of gene expression, ATP biosynthesis and maintenance of cytoskeleton. This dataset represents the largest library of AMPylated human proteins reported to date and a foundation for substrate-specific investigations that can ultimately decipher the complex biological networks involved in eukaryotic AMPylation.

2015-12-02 | PXD002601 | Pride

Xenograft mouse study in C57BL6/SCID mice using A431 cells

Project description:In this study four groups involving, Control arm, Rapamycin arm, Nimotuzumab arm and the Combination group were involved. Four tumors from each group was evaluated for microarray analysis they were the two largest and two smallest from each group. Agilent one-color experiment,Organism: Human ,Agilent-Custom Whole Genome Human 8x60k designed by Genotypic Technology Pvt. Ltd. (AMADID: 027114) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)

2011-10-20 | GSE32333 | GEO

Xenograft mouse study in C57BL6/SCID mice using A431 cells

2011-10-19 | E-GEOD-32333 | biostudies-arrayexpress

Valero2006_Adenine_TernaryCycle

Project description:This a model from the article: A kinetic study of a ternary cycle between adenine nucleotides. Valero E, Varón R, García-Carmona F FEBS J. [2006 Aug;273(15):3598-613 16884499 , Abstract: In the present paper, a kinetic study is made of the behavior of a moiety-conserved ternary cycle between the adenine nucleotides. The system contains the enzymes S-acetyl coenzyme A synthetase, adenylate kinase and pyruvate kinase, and converts ATP into AMP, then into ADP and finally back to ATP. L-Lactate dehydrogenase is added to the system to enable continuous monitoring of the progress of the reaction. The cycle cannot work when the only recycling substrate in the reaction medium is AMP. A mathematical model is proposed whose kinetic behavior has been analyzed both numerically by integration of the nonlinear differential equations describing the kinetics of the reactions involved, and analytically under steady-state conditions, with good agreement with the experimental results being obtained. The data obtained showed that there is a threshold value of the S-acetyl coenzyme A synthetase/adenylate kinase ratio, above which the cycle stops because all the recycling substrate has been accumulated as AMP, never reaching the steady state. In addition, the concept of adenylate energy charge has been applied to the system, obtaining the enabled values of the rate constants for a fixed adenylate energy charge value and vice versa.

2009-08-19 | BIOMD0000000231 | BioModels

Gene regulation by CnpB in Mycobacterium tuberculosis

Project description:We have previously reported that Mycobacterium tuberculosis Rv2837c (cnpB) encodes a phosphodiesterase that specifically cleaves cyclic di-AMP (c-di-AMP) into AMP. Deletion of cnpB results in significant virulence attenuation in a mouse pulmonary infection model, which is very likely due to the significantly elevated c-di-AMP levels as overexpression of Mtb diadenylate cyclase, disA, also leads to a similar outcome. An earlier study also demonstrated that CnpB functions similarly to E. coli oligoribonuclease (Orn) that hydrolyzes 2-5-mer nanoRNAs (short oligonucleotides of five residues or shorter in length) except that CnpB prefers 2-mer nanoRNA as a substrate. Additionally, a recent report showed that CnpB also degrades cyclic di-GMP (c-di-GMP), although we demonstrated that CnpB prefers c-di-AMP to c-di-GMP according to an in vitro enzymatic kinetics analysis In this study, we initially attempted to determine c-di-AMP-mediated gene regulation in Mtb by comparing the expression profiles between WT and ∆cnpB using RNA-Seq. We found that the CRISPR-Cas system of M. tuberculosis was highly upregulated by deletion of cnpB.

2018-02-27 | GSE102816 | GEO

Chaperone dependent coordination of nutrient sensing and energy metabolism by mTORC2

Project description:mTORC2 senses nutrients and coordinates substrate metabolism and macromolecule synthesis program with the availability of external nutrient availability. Knockdown of mTORC2 components and its chaperone partners impairs both nutrient sensing and downstrem metabolism/growth programs.

2020-01-23 | GSE93948 | GEO

HYPE mediated AMPylation site profiling with YnATP in human lysates

Project description:We describe here the first example of global chemoproteomic screening for HYPE mediated AMPylation sites of human proteins. Catalytically active mutant HYPE E234G was applied in combination with an alkynylated ATP and an alkynyl-biotinylated side ID reagent for capture of chemoenzymatically tagged proteins. AMPylation sites were detected by shotgun proteomics performed on a Q-Exactive instrument.

2015-12-02 | PXD003053 | Pride

Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group B Streptococcus

Project description:Streptococcus agalactiae is among the few pathogens that have not developed resistance to ß-lactam antibiotics despite decades of clinical use. The molecular basis of this long-lasting susceptibility has not been investigated, and it is uncertain whether specific mechanisms constraint the emergence of resistance. In this study, we first report a conserved role of the signaling nucleotide cyclic-di-AMP in the sensitivity of S. agalactiae to ß-lactam. Specifically, we demonstrate that inactivation of the phosphodiesterase GdpP confers ß-lactam tolerance. Characterizing the signaling pathway revealed an antagonistic regulation by the transcriptional factor BusR, which is activated by c-di-AMP and negatively regulates ß-lactam susceptibility. Furthermore, we show that simultaneous inhibition of osmolyte transporters activity and transcription by c-di-AMP has an additive effect, sustaining ß-lactam tolerance. Finally, transposon mutagenesis for ß-lactam reduced susceptibility reveals a convergent pattern of mutations, including in the KhpAB small RNA chaperone and the protein S immunomodulator. Overall, our findings suggest mechanisms that may foster antibiotic resistance in S. agalactiae and demonstrate that c-di-AMP acts as a turgor pressure rheostat, coordinating an integrated response to cell wall weakening due to ß-lactam activity.

2024-04-25 | GSE262190 | GEO

Proteomics Analysis of the Mechanism of AMP-17 against Candida albicans

Project description:Candida albicans is the most common human fungal pathogen in immunocompromised individuals. With the emergence of clinical fungal resistance, there is an urgent demand to develop novel antifungal agents. The antibacterial peptide (AMP) is an important component in the innate immune system and has a good therapeutic effect on patients infected with microorganisms. AMP-17, a novel AMP from Musca domestica, has an antifungal effect against C. albicans, but the mechanism of antifungal action remains unclear. In this study, we performed proteomic analysis of C. albicans treated AMP-17 and No drug using a combination of a series of cutting-edge technologies, including TMT labeling, HPLC classification and quantitative proteomics based on mass spectrometry. A total of 3,931 proteins were identified, of which 3,600 contained quantitative information. With a 1.5-fold change threshold and a t-test p-value <0.05 as a standard, 423 differentially expressed proteins (DEPs) were up-regulated and 180 differentially expressed proteins (DEPs) were down-regulated in the quantitative AMP_17/con comparison group. In these DEPs, proteins associated with ergosterol biosynthesis, oxidative stress and cell wall were identified as significantly up-regulated, while proteins involved in fatty acid biosynthesis were identified as significantly down-regulated. In addition, using the KEGG enrichment assay, seven significant KEGG pathways were identified, primarily involved in oxidative phosphorylation, propionic acid metabolism, and fatty acid metabolism. These results showed that AMP-17 induces a complex organism response to C. albicans, indicating that AMP-17 can inhibit growth by affecting multiple targets in C. albicans cells.

2019-10-23 | PXD015469 | Pride

Expression data of A2058-TET2WT, A2058-TET2M, and Mock cells treated under high-g and normal-g

Project description:Diabetes is a complex metabolic syndrome characterized by prolonged high blood glucose levels. It is known that diabetes is associated with an elevated risk of cancer, however, the underlying molecular mechanisms are largely unknown. In particular, it remains unclear as to how hyperglycemia may affect epigenetic checkpoints and tumor suppressor pathways, thus enabling oncogenic transformation. Here we show that long-term hyperglycemic conditions adversely impact the anti-tumor epigenetic mark DNA 5-hydroxymethylcytosine (5hmC) through direct regulation of the tumor suppressor and DNA 5mC hydroxymethylase, TET2. We identify TET2 as a novel substrate of the AMP-activated kinase (AMPK). The microarray data is used to study genes that are differentially regulated by glucose through TET2.

2018-07-15 | GSE85990 | GEO

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