Mapping the tandem mass spectrometric characteristics of citrulline‐containing peptides

Steckel, Arnold; Uray, Katalin; Turiák, Lilla; Gömöry, Ágnes; Drahos, László; Hudecz, Ferenc; Schlosser, Gitta

doi:10.1002/rcm.8105

Cited by 12 publications

(22 citation statements)

References 24 publications

(46 reference statements)

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“…Interestingly, no BP* was observed for any Aaa-Cit connection further confirming that Cit-Zzz cleavage is preferred instead in case of tryptic peptides. Aspartic acid effect [19] was also not prevalent among deiminated peptides used in this study (Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Proline effect which results in intensive peaks corresponding to the cleavage at the N -terminus of Pro residues (Aaa-Pro) due to the higher basicity of Pro has been long time known for tryptic peptides [18]. We previously reported a similar phenomenon for Cit residues upon fragmenting Cit-containing model peptides, but in these cases, the cleavage occurred at the C -terminus of Cit residues (Cit-Aaa) [19] (Figure 1) as in the case of the aspartic acid effect, where the preferred cleavage is at the Asp-Aaa linkage [18]. However, our previous sample size was not adequate (only 11 citrulline-containing synthetic model peptides were used), data were lacking on the overall occurrence, and the hypothesis was not tested on real proteomic samples before.…”

Section: Introductionmentioning

confidence: 99%

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Citrulline Effect Is a Characteristic Feature of Deiminated Peptides in Tandem Mass Spectrometry

Steckel

Schlosser

2019

J. Am. Soc. Mass Spectrom.

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Tandem mass spectrometry of peptides is of utmost importance in proteomics. Collision-induced dissociation usually generates y type fragment ion series from tryptic peptides, carrying information on their primary structure. Amino acid side chains or differences in their basicity could alter fragmentation processes considerably. The well-known proline effect is a cleavage preference at the N -terminus of proline residues in peptides, usually yielding a very abundant y ion while suppressing others. Previously, we reported a similar phenomenon occurring at the C -terminus of citrulline residues and coined the term Cit effect. To confirm the presence of Cit effect in large proteomic datasets, we analyzed 293 peptides containing Cit residues based on the human proteome database mining work of Lee et al. (2018). The occurrence of Cit effect was found to be 44%. Comparing bond scissions at the amide linkage between Cit-Zzz (citrulline followed by a specified residue) to Aaa 1 -Aaa 2 (Aaa can be any residue except Cit), 5 Cit-Zzz cleavages were significantly (CL = 95.0%) more frequent in > 85% of the cases in terms of relative sequential base beak occurrence. We used Pro effect to compare with Cit effect and obtained very similar results. On the other hand, our study showed that Cit effect is slightly inferior in the overall incidence to Pro effect (50% vs. 33%, CL = 95%) among deiminated peptides when Pro residues were also present in the sequence. Our results suggest that Cit effect is a characteristic feature and a possible biasing factor of deiminated peptides which can confirm the position of citrullination sites. Electronic supplementary material The online version of this article (10.1007/s13361-019-02271-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Citrulline Effect Is a Characteristic Feature of Deiminated Peptides in Tandem Mass Spectrometry

Steckel

Schlosser

2019

J. Am. Soc. Mass Spectrom.

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“…The technical advance of CID type of fragmentation stretched the capabilities of mass spectrometry‐based proteomics technology. However, it should accompany good practices for localization of citrullination sites in peptides, which requires a full ion series (all b and y ions of −43 Da) around modified residue …”

Section: Mass Spectrometry Applied To the Study Of Citrullination In mentioning

confidence: 99%

“…However, it should accompany good practices for localization of citrullination sites in peptides, which requires a full ion series (all b and y ions of −43 Da) around modified residue. 39 Later, as an alternative approach, Creese and colleagues combined CID with ETD, as ETD cleaves randomly along the peptide backbone, while often leaving side chains and modifications intact. 34 If neutral loss of isocyanic acid is observed in the CID spectrum, ETD of the parent ion is performed, which improved the identification and localization of the modification site.…”

Section: Neutral Loss Of Isocyanic Acid In Peptide Collision-inducementioning

confidence: 99%

Insights into the study and origin of the citrullinome in rheumatoid arthritis

Fert-Bober

Darrah

Andrade

2019

Immunological Reviews

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The presence of autoantibodies and autoreactive T cells to citrullinated proteins and citrullinating enzymes in patients with rheumatoid arthritis (RA), together with the accumulation of citrullinated proteins in rheumatoid joints, provides substantial evidence that dysregulated citrullination is a hallmark feature of RA. However, understanding mechanisms that dysregulate citrullination in RA has important challenges. Citrullination is a normal process in immune and non‐immune cells, which is likely activated by different conditions (eg, inflammation) with no pathogenic consequences. In a complex inflammatory environment such as the RA joint, unique strategies are therefore required to dissect specific mechanisms involved in the abnormal production of citrullinated proteins. Here, we will review current models of citrullination in RA and discuss critical components that, in our view, are relevant to understanding the accumulation of citrullinated proteins in the RA joint, collectively referred to as the RA citrullinome. In particular, we will focus on potential caveats in the study of citrullination in RA and will highlight methods to precisely detect citrullinated proteins in complex biological samples, which is a confirmatory approach to mechanistically link the RA citrullinome with unique pathogenic pathways in RA.

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“…We also described a facile cleavage C -terminal to Cit, which could be explained by a loss of isocyanic acid followed by a lactam formation ( Scheme 1 ). 30 Thus, we also synthesized peptides where X or Z are substituted for ornithines (O) or lysines (K) to compare the MS/MS behavior of these residues to that of Cit and Hci.…”

Section: Introductionmentioning

confidence: 99%

Quantification of the Effect of Citrulline and Homocitrulline Residues on the Collision-Induced Fragmentation of Peptides

Steckel

Borbély

Uray

et al. 2020

J. Am. Soc. Mass Spectrom.

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Posttranslational modifications of proteins like citrullination and carbamylation are associated with several diseases. Detailed analytical characterization of citrullinated and carbamylated proteins or peptides could be difficult due to the low concentration of the analytes in complex biological samples. High structural similarity and chemical behavior of citrullinated and carbamylated residues also pose a challenge. We previously reported the “citrulline effect” phenomenon that is manifested in the generation of intense y type ions originating from Cit-Zzz amide bond scissions in collision-induced dissociation tandem mass spectra of citrullinated tryptic peptides. In this study, we created a rigorous tryptic-like model system of both citrulline and homocitrulline-containing peptides that included appropriate and well-defined controls and fragment analogues to quantify the citrulline effect and investigate whether there is an effect for homocitrulline residues as well. Our results show that citrulline residues significantly increased fragmentation at their C-terminus relatively independent of the identity of the following amino acid. In comparison, homocitrulline residues displayed inconclusive results at the same energies. However, the strength of effects was dependent on collision energy and the position of citrulline and homocitrulline in the sequences. As newer software algorithms tend to observe structure–intensity relationships during annotation, this finding increases reliable identification of modified proteins/peptides.

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Mapping the tandem mass spectrometric characteristics of citrulline‐containing peptides

Cited by 12 publications

References 24 publications

Citrulline Effect Is a Characteristic Feature of Deiminated Peptides in Tandem Mass Spectrometry

Citrulline Effect Is a Characteristic Feature of Deiminated Peptides in Tandem Mass Spectrometry

Insights into the study and origin of the citrullinome in rheumatoid arthritis

Quantification of the Effect of Citrulline and Homocitrulline Residues on the Collision-Induced Fragmentation of Peptides

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