title: The Different Conformational States of Tissue Transglutaminase Have Opposing Affects on Cell Viability.
abstract: Tissue transglutaminase (tTG) is an acyltransferase/GTP-binding protein that contributes to the development of various diseases. In human cancer cells, tTG activates signaling pathways that promote cell growth and survival, whereas in other disorders (i.e. neurodegeneration), overexpression of tTG enhances cell death. Therefore, it is important to understand how tTG is differentially regulated and functioning to promote diametrically distinct cellular outcomes. Previous structural studies revealed that tTG adopts either a nucleotide-bound closed conformation or a transamidation-competent open conformation. Here we provide evidence showing that these different conformational states determine whether tTG promotes, or is detrimental to, cell survival, with the open conformation of the protein being responsible for inducing cell death. First, we demonstrate that a nucleotide binding-defective form of tTG, which has previously been shown to induce cell death, assumes an open conformation in solution as assessed by an enhanced sensitivity to trypsin digestion and by small angle x-ray scattering (SAXS) analysis. We next identify two pairs of intramolecular hydrogen bonds that, based on existing x-ray structures, are predicted to form between the most C-terminal β-barrel domain and the catalytic core domain of tTG. By disrupting these hydrogen bonds, we are able to generate forms of tTG that constitutively assume an open conformation and induce apoptosis. These findings provide important insights into how tTG participates in the pathogenesis of neurodegenerative diseases, particularly with regard to the actions of a C-terminal truncated form of tTG (TG-Short) that has been linked to such disorders and induces apoptosis by assuming an open-like conformation.
authors.affiliation: From the Department of Molecular Medicine and.
authors.forename: Garima
authors.initials: G
authors.lastname: Singh
authors.affiliation: From the Department of Molecular Medicine and.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Molecular Medicine and.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: From the Department of Molecular Medicine and the Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853 rac1@cornell.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: From the Department of Molecular Medicine and.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: apoptosis; cell death; conformational change; protein cross-linking; small-angle x-ray scattering (SAXS); transglutaminase