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Mining the Human Tissue Proteome for Protein Citrullination
Tech Univ Munich, Chair Prote & Bioanalyt, Emil Erlenmeyer Forum 5, D-85354 Freising Weihenstephan, Germany.;Natl Chung Hsing Univ, Grad Inst Biotechnol, Taichung, Taiwan.;Acad Sinica, Mol & Biol Agr Sci Program, Taiwan Int Grad Program, Taipei, Taiwan.;Natl Chung Hsing Univ, Taipei, Taiwan..
Tech Univ Munich, Chair Prote & Bioanalyt, Emil Erlenmeyer Forum 5, D-85354 Freising Weihenstephan, Germany..
Tech Univ Munich, Chair Prote & Bioanalyt, Emil Erlenmeyer Forum 5, D-85354 Freising Weihenstephan, Germany..ORCID iD: 0000-0002-9224-3258
Tech Univ Munich, Chair Prote & Bioanalyt, Emil Erlenmeyer Forum 5, D-85354 Freising Weihenstephan, Germany..
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2018 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 17, no 7, p. 1378-1391Article in journal (Refereed) Published
Abstract [en]

Citrullination is a posttranslational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations, and while the modification has been linked to several diseases, including rheumatoid arthritis (RA) and cancer, its physiological or pathophysiological roles remain largely unclear. In part, this is owing to limitations in available methodology to robustly enrich, detect, and localize the modification. As a result, only a few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass-spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of similar to 70 million tandem mass spectra yielded similar to 13,000 candidate spectra, which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized similar to 2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new, and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in the brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes. Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins, arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2018. Vol. 17, no 7, p. 1378-1391
Keywords [en]
Post-translational modifications, Tissues, Data evaluation, Omics, Tandem Mass Spectrometry, citrullination, human proteome, peptidylarginine deiminase, synthetic peptides
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-232406DOI: 10.1074/mcp.RA118.000696ISI: 000437410300010PubMedID: 29610271Scopus ID: 2-s2.0-85049241062OAI: oai:DiVA.org:kth-232406DiVA, id: diva2:1235630
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170726

Available from: 2018-07-26 Created: 2018-07-26 Last updated: 2020-01-10Bibliographically approved

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