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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

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1437-4315
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Volume 390, Issue 2

Issues

Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4

Maria E. Stensland
  • 1Centre for Immune Regulation, Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sylvie Pollmann
  • 2Centre for Immune Regulation, Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Øyvind Molberg / Ludvig M. Sollid
  • 4Centre for Immune Regulation, Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Burkhard Fleckenstein
  • 5Centre for Immune Regulation, Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2008-11-29 | DOI: https://doi.org/10.1515/BC.2009.019

Abstract

Enzymes of the peptidylarginine deiminase (PAD) family catalyze the posttranslational deimination of polypeptide-bound arginine residues. Here, we report the selection of peptide substrates by PAD-4, an isoform thought to be involved in the pathogenesis of rheumatoid arthritis. First, we investigated whether PAD-4-mediated deimination is influenced by the nature of amino acid residues flanking the targeted arginine. Using two peptide substrates, residues in positions -2, -1, +1, and +2 relative to the central arginine targeted by PAD-4 were systematically replaced by all natural l-amino acids except cysteine. Each peptide was treated with recombinant human PAD-4 and deimination was analyzed by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. In all four flanking positions, amino acids which positively or negatively influenced deimination were identified. We next designed peptides with expected high or low deimination rates and determined their Km and kcat values. These peptides showed PAD-4 substrate behavior as predicted, demonstrating that residues flanking the targeted arginine are important for deimination. Further truncation of peptide substrates suggested additional effects on deimination by residues outside the -2 to +2 region. Finally, we observed that a methylated lysine residue flanking the targeted arginine influences PAD-4-mediated deimination, also suggesting that posttranslational modifications can affect substrate efficiency.

Keywords: amino acid sequence; citrullination; enzyme specificity; matrix-assisted laser desorption-ionization time-of-flight mass spectrometry

About the article

Corresponding author


Received: 2008-08-21

Accepted: 2008-10-30

Published Online: 2008-11-29

Published in Print: 2009-02-01


Citation Information: Biological Chemistry, Volume 390, Issue 2, Pages 99–107, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2009.019.

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