Tissue transglutaminase is a multifunctional BH3-only protein

J Biol Chem. 2004 Dec 24;279(52):54783-92. doi: 10.1074/jbc.M410938200. Epub 2004 Oct 12.

Abstract

Tissue transglutaminase (TG2) protein accumulates to high levels in cells during early stages of apoptosis both in vivo and in vitro. The analysis of the TG2 primary sequence showed the presence of an eight amino acid domain, sharing 70% identity with the Bcl-2 family BH3 domain. Cell-permeable peptides, mimicking the domain sequence, were able to induce Bax conformational change and translocation to mitochondria, mitochondrial depolarization, release of cytochrome c, and cell death. Moreover, we found that the TG2-BH3 peptides as well as TG2 itself were able to interact with the pro-apoptotic Bcl-2 family member Bax, but not with anti-apoptotic members Bcl-2 and Bcl-X(L). Mutants in the TG2-BH3 domain failed to sensitize cells toward apoptosis. In TG2-overexpressing cells about half of the protein is localized on the outer mitochondrial membrane where, upon cell death induction, it cross-links many protein substrates including Bax. TG2 is the first member of a new subgroup of multifunctional BH3-only proteins showing a large mass size (80 kDa) and enzymatic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • Binding Sites
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Membrane Permeability
  • Cyclosporine / pharmacology
  • Cytochromes c / metabolism
  • GTP-Binding Proteins / chemistry*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / physiology*
  • Humans
  • Membrane Proteins / physiology
  • Mitochondria / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutagenesis
  • Neuroblastoma
  • Protein Conformation
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Sequence Alignment
  • Transfection
  • Transglutaminases / chemistry*
  • Transglutaminases / genetics
  • Transglutaminases / physiology*
  • Tumor Cells, Cultured
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein

Substances

  • BAK1 protein, human
  • BAX protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Cyclosporine
  • Cytochromes c
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins