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Article ; Online: Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in vivo Experiments.

Martinelli, Paola / Schaaf, Otmar / Mantoulidis, Andreas / Martin, Laetitia J / Fuchs, Julian E / Bader, Gerd / Gollner, Andreas / Wolkerstorfer, Bernhard / Rogers, Catherine / Balıkçı, Esra / Lipp, Jesse J / Mischerikow, Nikolai / Doebel, Sandra / Gerstberger, Thomas / Sommergruber, Wolfgang / Huber, Kilian V M / Böttcher, Jark

ChemMedChem

2023 Volume 18, Issue 6, Page(s) e202200686

Abstract: The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe ... ...

Abstract	The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.
MeSH term(s)	Animals ; Mice ; Cell Proliferation ; Gene Expression Regulation ; Lung Neoplasms ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism
Chemical Substances	Nuclear Proteins ; Transcription Factors ; fetal Alzheimer antigen
Language	English
Publishing date	2023-02-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202200686
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Article ; Online: Targeted large-scale analysis of protein acetylation.

Mischerikow, Nikolai / Heck, Albert J R

Proteomics

2011 Volume 11, Issue 4, Page(s) 571–589

Abstract: Protein modifications are biologically important events that may be studied by mass spectrometry-based high-throughput proteome analyses. In recent years, several new technologies have emerged that have widened and deepened the targeted analysis of one ... ...

Abstract	Protein modifications are biologically important events that may be studied by mass spectrometry-based high-throughput proteome analyses. In recent years, several new technologies have emerged that have widened and deepened the targeted analysis of one important, albeit functionally ill-defined modification, namely protein acetylation. This modification can take place both co- and post-translationally by the transfer of acetyl groups under the catalysis of acetyltransferases. The acetyl group can modify either the α-amino group at the N-terminus, so-called N-terminal acetylation, or the ε-amino group on the side chain of lysine residues. Here, we review several emerging targeted technologies to chart both N-terminal acetylation as well as acetylation at the lysine side chain, on a proteome-wide scale, highlighting in particular studies that have expanded the biological knowledge on the appearance and function of these common but functionally still less investigated co- and post-translational modifications.
MeSH term(s)	Acetylation ; Animals ; Chromatography, Liquid ; High-Throughput Screening Assays/methods ; Humans ; Molecular Probe Techniques ; Protein Processing, Post-Translational ; Proteins/analysis ; Proteins/chemistry ; Proteins/metabolism ; Proteomics/methods
Chemical Substances	Proteins
Language	English
Publishing date	2011-02
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.201000397
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Article: Targeted large-scale analysis of protein acetylation

Mischerikow, Nikolai / Heck, Albert J.R

Proteomics. 2011 Feb., v. 11, no. 4

2011

Abstract	Protein modifications are biologically important events that may be studied by mass spectrometry-based high-throughput proteome analyses. In recent years, several new technologies have emerged that have widened and deepened the targeted analysis of one important, albeit functionally ill-defined modification, namely protein acetylation. This modification can take place both co- and post-translationally by the transfer of acetyl groups under the catalysis of acetyltransferases. The acetyl group can modify either the α-amino group at the N-terminus, so-called N-terminal acetylation, or the ε-amino group on the side chain of lysine residues. Here, we review several emerging targeted technologies to chart both N-terminal acetylation as well as acetylation at the lysine side chain, on a proteome-wide scale, highlighting in particular studies that have expanded the biological knowledge on the appearance and function of these common but functionally still less investigated co- and post-translational modifications.
Language	English
Dates of publication	2011-02
Size	p. 571-589.
Publishing place	Wiley-VCH Verlag
Document type	Article
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.201000397
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Article ; Online: A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

Kofink, Christiane / Trainor, Nicole / Mair, Barbara / Wöhrle, Simon / Wurm, Melanie / Mischerikow, Nikolai / Roy, Michael J / Bader, Gerd / Greb, Peter / Garavel, Géraldine / Diers, Emelyne / McLennan, Ross / Whitworth, Claire / Vetma, Vesna / Rumpel, Klaus / Scharnweber, Maximilian / Fuchs, Julian E / Gerstberger, Thomas / Cui, Yunhai /

Gremel, Gabriela / Chetta, Paolo / Hopf, Stefan / Budano, Nicole / Rinnenthal, Joerg / Gmaschitz, Gerhard / Mayer, Moriz / Koegl, Manfred / Ciulli, Alessio / Weinstabl, Harald / Farnaby, William

Nature communications

2022 Volume 13, Issue 1, Page(s) 5969

Abstract: Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target ... ...

Abstract	Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
MeSH term(s)	Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proteolysis ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemical Substances	Nuclear Proteins ; SMARCA2 protein, human ; Transcription Factors ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; Adenosine Triphosphatases (EC 3.6.1.-) ; SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; VHL protein, human (EC 6.3.2.-)
Language	English
Publishing date	2022-10-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33430-6
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Article ; Online: Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS

Bröker, Joachim / Waterson, Alex G / Smethurst, Chris / Kessler, Dirk / Böttcher, Jark / Mayer, Moriz / Gmaschitz, Gerhard / Phan, Jason / Little, Andrew / Abbott, Jason R / Sun, Qi / Gmachl, Michael / Rudolph, Dorothea / Arnhof, Heribert / Rumpel, Klaus / Savarese, Fabio / Gerstberger, Thomas / Mischerikow, Nikolai / Treu, Matthias /

Herdeis, Lorenz / Wunberg, Tobias / Gollner, Andreas / Weinstabl, Harald / Mantoulidis, Andreas / Krämer, Oliver / McConnell, Darryl B / W Fesik, Stephen

Journal of medicinal chemistry

2022 Volume 65, Issue 21, Page(s) 14614–14629

Abstract: Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for ... ...

Abstract	Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS
MeSH term(s)	Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Genes, ras ; Mutation ; Neoplasms/genetics ; Cysteine
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cysteine (K848JZ4886) ; KRAS protein, human
Language	English
Publishing date	2022-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01120
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Article ; Online: Comparative assessment of site assignments in CID and electron transfer dissociation spectra of phosphopeptides discloses limited relocation of phosphate groups.

Mischerikow, Nikolai / Altelaar, A F Maarten / Navarro, J Daniel / Mohammed, Shabaz / Heck, Albert J R

Molecular & cellular proteomics : MCP

2010 Volume 9, Issue 10, Page(s) 2140–2148

Abstract: In large scale mass spectrometry-based phosphoproteomics, a current bottleneck is the unambiguous assignment of the phosphorylation site within the peptide. An additional problem is that it has been reported that under conditions wherein peptide ions are ...

Abstract	In large scale mass spectrometry-based phosphoproteomics, a current bottleneck is the unambiguous assignment of the phosphorylation site within the peptide. An additional problem is that it has been reported that under conditions wherein peptide ions are collisionally activated the phosphate group may migrate to a nearby phosphate group acceptor, thus causing ambiguity in site assignment. Here, we generated and analyzed a statistically significant number of phosphopeptides. Starting with a human cell lysate, we obtained via strong cation exchange fractionation nearly pure phosphopeptide pools from trypsin and Lys-N digestions. These pools were subjected to nano-LC-MS using an Orbitrap mass spectrometer that is equipped with both CID and electron transfer dissociation with supplemental activation (ETcaD) functionality. We configured a method to obtain sequentially both ETcaD and CID spectra for each peptide ion. We exploited the resistant nature of ETcaD toward rearrangement of phosphate groups to evaluate whether there is potentially phosphate group relocation occurring during CID. We evaluated a number of peptide and spectral annotation properties and found that for ∼75% of the sequenced phosphopeptides the assigned phosphosite was unmistakably identical for both the ETcaD and CID spectra. For the remaining 25% of the sequenced phosphopeptides, we also did not observe evident signs of relocation, but these peptides exhibited signs of ambiguity in site localization, predominantly induced by factors such as poor fragmentation, sequences causing inefficient fragmentation, and generally poor spectrum quality. Our data let us derive the conclusion that both for trypsin- and Lys-N-generated peptides there is little relocation of phosphate groups occurring during CID.
MeSH term(s)	Electron Transport ; Mass Spectrometry ; Phosphates/chemistry ; Phosphopeptides/chemistry ; Phosphopeptides/metabolism ; Phosphorylation
Chemical Substances	Phosphates ; Phosphopeptides
Language	English
Publishing date	2010-03-16
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.M900619-MCP200
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Article ; Online: Identification of Pep4p as the protease responsible for formation of the SAGA-related SLIK protein complex.

Spedale, Gianpiero / Mischerikow, Nikolai / Heck, Albert J R / Timmers, H T Marc / Pijnappel, W W M Pim

The Journal of biological chemistry

2010 Volume 285, Issue 30, Page(s) 22793–22799

Abstract: The Saccharomyces cerevisiae Spt-Ada-Gcn5 acetyltransferase (SAGA) protein complex is a coactivator for transcription by RNA polymerase II and has various activities, including acetylation and deubuiqitination of histones and recruitment of TATA-binding ... ...

Abstract	The Saccharomyces cerevisiae Spt-Ada-Gcn5 acetyltransferase (SAGA) protein complex is a coactivator for transcription by RNA polymerase II and has various activities, including acetylation and deubuiqitination of histones and recruitment of TATA-binding protein to promoters. The Spt7p subunit is subject to proteolytic cleavage at its C terminus resulting in removal of the Spt8p-binding domain and generation of the SAGA-related SALSA/SAGA-like (SLIK) protein complex. Here, we report identification of the protease responsible for this cleavage. Screening of a protease knock-out collection revealed PEP4 to be required for cleavage of Spt7p within SAGA in vitro. Endogenous formation of truncated Spt7p was abolished in cells lacking PEP4. Purified Pep4p but not catalytic dead mutant Pep4p or unrelated Prc1p protease specifically cleaved Spt7p within SAGA into SLIK-related Spt7p. Interestingly, SAGA lacking Spt8p was more sensitive to Pep4p-mediated truncation of Spt7p, suggesting that Spt8p counteracted its own release from SAGA. Strains mimicking constitutive SLIK formation showed increased resistance to rapamycin treatment, suggesting a role for SLIK in regulating cellular responses to nutrient stress.
MeSH term(s)	Aspartic Acid Endopeptidases/deficiency ; Aspartic Acid Endopeptidases/genetics ; Aspartic Acid Endopeptidases/metabolism ; Drug Resistance, Fungal ; Gene Knockout Techniques ; Protein Subunits/metabolism ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sirolimus/pharmacology ; Trans-Activators/chemistry ; Trans-Activators/metabolism
Chemical Substances	Protein Subunits ; SAGA complex, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Trans-Activators ; PEP4 protein, S cerevisiae (EC 3.4.23.) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2010-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.108787
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Article: Identification of Pep4p as the Protease Responsible for Formation of the SAGA-related SLIK Protein Complex

Spedale, Gianpiero / Mischerikow, Nikolai / Heck, Albert J.R / Timmers, H.T. Marc / Pijnappel, W.W.M. Pim

Journal of biological chemistry. 2010 July 23, v. 285, no. 30

2010

Abstract	The Saccharomyces cerevisiae Spt-Ada-Gcn5 acetyltransferase (SAGA) protein complex is a coactivator for transcription by RNA polymerase II and has various activities, including acetylation and deubuiqitination of histones and recruitment of TATA-binding protein to promoters. The Spt7p subunit is subject to proteolytic cleavage at its C terminus resulting in removal of the Spt8p-binding domain and generation of the SAGA-related SALSA/SAGA-like (SLIK) protein complex. Here, we report identification of the protease responsible for this cleavage. Screening of a protease knock-out collection revealed PEP4 to be required for cleavage of Spt7p within SAGA in vitro. Endogenous formation of truncated Spt7p was abolished in cells lacking PEP4. Purified Pep4p but not catalytic dead mutant Pep4p or unrelated Prc1p protease specifically cleaved Spt7p within SAGA into SLIK-related Spt7p. Interestingly, SAGA lacking Spt8p was more sensitive to Pep4p-mediated truncation of Spt7p, suggesting that Spt8p counteracted its own release from SAGA. Strains mimicking constitutive SLIK formation showed increased resistance to rapamycin treatment, suggesting a role for SLIK in regulating cellular responses to nutrient stress.
Language	English
Dates of publication	2010-0723
Size	p. 22793-22799.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article ; Online: The generating function of CID, ETD, and CID/ETD pairs of tandem mass spectra: applications to database search.

Kim, Sangtae / Mischerikow, Nikolai / Bandeira, Nuno / Navarro, J Daniel / Wich, Louis / Mohammed, Shabaz / Heck, Albert J R / Pevzner, Pavel A

Molecular & cellular proteomics : MCP

2010 Volume 9, Issue 12, Page(s) 2840–2852

Abstract: Recent emergence of new mass spectrometry techniques (e.g. electron transfer dissociation, ETD) and improved availability of additional proteases (e.g. Lys-N) for protein digestion in high-throughput experiments raised the challenge of designing new ... ...

Abstract	Recent emergence of new mass spectrometry techniques (e.g. electron transfer dissociation, ETD) and improved availability of additional proteases (e.g. Lys-N) for protein digestion in high-throughput experiments raised the challenge of designing new algorithms for interpreting the resulting new types of tandem mass (MS/MS) spectra. Traditional MS/MS database search algorithms such as SEQUEST and Mascot were originally designed for collision induced dissociation (CID) of tryptic peptides and are largely based on expert knowledge about fragmentation of tryptic peptides (rather than machine learning techniques) to design CID-specific scoring functions. As a result, the performance of these algorithms is suboptimal for new mass spectrometry technologies or nontryptic peptides. We recently proposed the generating function approach (MS-GF) for CID spectra of tryptic peptides. In this study, we extend MS-GF to automatically derive scoring parameters from a set of annotated MS/MS spectra of any type (e.g. CID, ETD, etc.), and present a new database search tool MS-GFDB based on MS-GF. We show that MS-GFDB outperforms Mascot for ETD spectra or peptides digested with Lys-N. For example, in the case of ETD spectra, the number of tryptic and Lys-N peptides identified by MS-GFDB increased by a factor of 2.7 and 2.6 as compared with Mascot. Moreover, even following a decade of Mascot developments for analyzing CID spectra of tryptic peptides, MS-GFDB (that is not particularly tailored for CID spectra or tryptic peptides) resulted in 28% increase over Mascot in the number of peptide identifications. Finally, we propose a statistical framework for analyzing multiple spectra from the same precursor (e.g. CID/ETD spectral pairs) and assigning p values to peptide-spectrum-spectrum matches.
MeSH term(s)	Algorithms ; Cell Line ; Databases, Protein ; Humans ; Peptide Mapping ; Tandem Mass Spectrometry/methods ; Trypsin/chemistry
Chemical Substances	Trypsin (EC 3.4.21.4)
Language	English
Publishing date	2010-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.M110.003731
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Article ; Online: Gaining efficiency by parallel quantification and identification of iTRAQ-labeled peptides using HCD and decision tree guided CID/ETD on an LTQ Orbitrap.

Mischerikow, Nikolai / van Nierop, Pim / Li, Ka Wan / Bernstein, Hans-Gert / Smit, August B / Heck, Albert J R / Altelaar, A F Maarten

The Analyst

2010 Volume 135, Issue 10, Page(s) 2643–2652

Abstract: Isobaric stable isotope labeling of peptides using iTRAQ is an important method for MS based quantitative proteomics. Traditionally, quantitative analysis of iTRAQ labeled peptides has been confined to beam-type instruments because of the weak detection ... ...

Abstract	Isobaric stable isotope labeling of peptides using iTRAQ is an important method for MS based quantitative proteomics. Traditionally, quantitative analysis of iTRAQ labeled peptides has been confined to beam-type instruments because of the weak detection capabilities of ion traps for low mass ions. Recent technical advances in fragmentation techniques on linear ion traps and the hybrid linear ion trap-orbitrap allow circumventing this limitation. Namely, PQD and HCD facilitate iTRAQ analysis on these instrument types. Here we report a method for iTRAQ-based relative quantification on the ETD enabled LTQ Orbitrap XL, which is based on parallel peptide quantification and peptide identification. iTRAQ reporter ion generation is performed by HCD, while CID and ETD provide peptide identification data in parallel in the LTQ ion trap. This approach circumvents problems accompanying iTRAQ reporter ion generation with ETD and allows quantitative, decision tree-based CID/ETD experiments. Furthermore, the use of HCD solely for iTRAQ reporter ion read out significantly reduces the number of ions needed to obtain informative spectra, which significantly reduces the analysis time. Finally, we show that integration of this method, both with existing CID and ETD methods as well as with existing iTRAQ data analysis workflows, is simple to realize. By applying our approach to the analysis of the synapse proteome from human brain biopsies, we demonstrate that it outperforms a latest generation MALDI TOF/TOF instrument, with improvements in both peptide and protein identification and quantification. Conclusively, our work shows how HCD, CID and ETD can be beneficially combined to enable iTRAQ-based quantification on an ETD-enabled LTQ Orbitrap XL.
MeSH term(s)	Chromatography, Reverse-Phase ; Humans ; Isotope Labeling ; Peptides/analysis ; Peptides/chemistry ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
Chemical Substances	Peptides
Language	English
Publishing date	2010-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	210747-8
ISSN	1364-5528 ; 0003-2654
ISSN (online)	1364-5528
ISSN	0003-2654
DOI	10.1039/c0an00267d
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