Isopeptidase activity of human transglutaminase 2: disconnection from transamidation and characterization by kinetic parameters

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• 作者：Róbert Király ; Kiruphagaran Thangaraju ; Zsófia Nagy ; Russell Collighan…
• 关键词：Human transglutaminase 2 ; Isopeptidase activity ; γ ; Glutamyl ; hydrolase ; Transamidation ; Regulation of activities ; Moonlighting enzyme
• 刊名：Amino Acids
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：48
• 期：1
• 页码：31-40
• 全文大小：674 KB
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• 作者单位：Róbert Király (1)
  Kiruphagaran Thangaraju (1)
  Zsófia Nagy (1)
  Russell Collighan (3)
  Zoltán Nemes (1)
  Martin Griffin (3)
  László Fésüs (1) (2)
  
  1. Department of Biochemistry and Molecular Biology, University of Debrecen, Egyetem tér 1., Debrecen, 4012, Hungary
  3. School of Life and Health Sciences, Aston University, Birmingham, UK
  2. MTA-DE Stem Cell, Apoptosis and Genomics Research Group of Hungarian Academy of Sciences, Faculty of Medicine, University of Debrecen, Egyetem tér 1., Debrecen, 4012, Hungary
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Analytical Chemistry
  Biochemical Engineering
  Life Sciences
  Proteomics
  Neurobiology
  
• 出版者：Springer Wien
• ISSN：1438-2199

文摘

Transglutaminase 2 (TG2) is a multifunctional protein with diverse catalytic activities and biological roles. Its best studied function is the Ca2+-dependent transamidase activity leading to formation of γ-glutamyl-ε-lysine isopeptide crosslinks between proteins and γ-glutamyl-amine derivatives. TG2 has a poorly studied isopeptidase activity cleaving these bonds. We have developed and characterised TG2 mutants which are significantly deficient in transamidase activity while have normal or increased isopeptidase activity (W332F) and vice versa (W278F). The W332F mutation led to significant changes of both the K _m and the V _max kinetic parameters of the isopeptidase reaction of TG2 while its calcium and GTP sensitivity was similar to the wild-type enzyme. The W278F mutation resulted in six times elevated amine incorporating transamidase activity demonstrating the regulatory significance of W278 and W332 in TG2 and that mutations can change opposed activities located at the same active site. The further application of our results in cellular systems may help to understand TG2-driven physiological and pathological processes better and lead to novel therapeutic approaches where an increased amount of crosslinked proteins correlates with the manifestation of degenerative disorders. Keywords Human transglutaminase 2 Isopeptidase activity γ-Glutamyl-hydrolase Transamidation Regulation of activities Moonlighting enzyme