Substrate preference of transglutaminase 2 revealed by logistic regression analysis and intrinsic disorder examination |
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Authors: | Csosz Eva Bagossi Peter Nagy Zoltan Dosztanyi Zsuzsanna Simon Istvan Fesus Laszlo |
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Institution: | 1 Department of Biochemistry and Molecular Biology, University of Debrecen, Egyetem ter 1, Life Science Building, 4010 Debrecen, Hungary 2 Department of Computer Science, University of Debrecen, Debrecen, Hungary 3 Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary 4 Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Debrecen, Hungary |
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Abstract: | Tissue transglutaminase (TG2) catalyzes the Ca2+-dependent posttranslational modification of proteins via formation of isopeptide bonds between their glutamine and lysine residues. Although substrate specificity of TG2 has been studied repeatedly at the sequence level, no clear consensus sequences have been determined so far. With the use of the extensive structural information on TG2 substrate proteins listed in TRANSDAB Wiki database†, a slight preference of TG2 for glutamine and lysine residues situated in turns could be observed. When the spatial environment of the favored glutamine and lysine residues was analyzed with logistic regression, the presence of specific amino acid patterns was identified. By using the occurrence of the predictor amino acids as selection criteria, several polypeptides were predicted and later identified as novel in vitro substrates for TG2. By studying the sequence of TG2 substrate proteins lacking available crystal structure, the strong favorable influence on substrate selection of the presence of substrate glutamine and lysine residues in intrinsically disordered regions could also be revealed. The collected structural data have provided novel understanding of how this versatile enzyme selects its substrates in various cell compartments and tissues. |
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Keywords: | AUC area under the curve CD delta carbon IDR intrinsically disordered region IGFBP insulin-like growth factor binding protein IκB inhibitory kappa B protein NZ zeta nitrogen ROC receiver operating characteristic TG2 tissue transglutaminase VIP vasoactive intestinal peptide 3D three-dimensional 5-BPA 5-biotinamido-penthylamine |
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