Structure of natural variant transglutaminase 2 reveals molecular basis of gaining stability and higher activity

PLoS One. 2018 Oct 15;13(10):e0204707. doi: 10.1371/journal.pone.0204707. eCollection 2018.

Abstract

Multi-functional transglutaminase 2 (TG2), which possesses protein cross-linking and GTP hydrolysis activities, is involved in various cellular processes, including apoptosis, angiogenesis, wound healing, and neuronal regeneration, and is associated with many human diseases, including inflammatory disease, celiac disease, neurodegenerative disease, diabetes, tissue fibrosis, and cancers. Although most biochemical and cellular studies have been conducted with the TG2 (G224) form, the TG2 (G224V) form has recently emerged as a putative natural variant of TG2. In this study, we characterized the putative natural form of TG2, TG2 (G224V), and through a new crystal structure of TG2 (G224V), we revealed how TG2 (G224V) gained stability and higher Ca2+-dependent activity than an artificial variant of TG2 (G224).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Calcium / metabolism
  • Catalytic Domain / genetics
  • Crystallography, X-Ray
  • Enzyme Stability / genetics
  • GTP-Binding Proteins / chemistry*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Genetic Variation
  • Humans
  • Kinetics
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Protein Glutamine gamma Glutamyltransferase 2
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transglutaminases / chemistry*
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*

Substances

  • Recombinant Proteins
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Calcium

Grants and funding

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (NRF-2017M3A9D8062960, NRF-2017R1D1A1B03035059, and NRF-2018R1A2B3008541) and a grant from the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI17C0155). E.M.J. was supported by the Brain Korea 21 (BK21) PLUS program of the Korean Ministry of Education, Science, and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.