A Tertiary Twist to the Transglutaminase Tale

T issue transglutaminase (TG2) is one of a family of enzymes that covalently crosslink proteins by binding a glutamine in one protein with a lysine in another [1]. There is strong evidence that links the deregulated expression of TG2 to a variety of diseases, and although the exact role of TG2 in neurodegenerative diseases is unclear [2], in celiac disease (CD), TG2 catalyses the formation of immunogenic peptides that play a crucial role in disease development [3,4]. Although x-ray crystal structures of transglutaminases have been reported previously, the catalytic site was hidden due to the protein's conformation. In this issue of PLoS Biology, a structure of TG2 is shown in which the enzyme is captured in its active state [5] with the catalytic site visible. This provides new insight into the mode of action of TG2 and offers novel opportunities for the development of TG2 inhibitors, which could have therapeutic applications. The paper also raises questions about what regulates TG2 activation and how TG2 activation influences disease development. Patients with celiac disease are intolerant to gluten proteins in wheat and related cereals [3,4]. In healthy individuals, the small intestine is lined with villi, which create a larger surface for the uptake of nutrients from food. In approximately 1% of the population in the Western Hemisphere, gluten induces inflammatory immune responses in the small intestine that lead to the disappearance of these villi. Malabsorption, retarded growth, diarrhea, and stomach ache can result, and these are the characteristic symptoms associated with CD [3,4]. CD typically develops in human leukocyte antigen (HLA)-DQ2– and/or HLA-DQ8–positive individuals [3,4]. HLA molecules are receptors that specifically bind peptides and present these to the T cells of the immune system. When such peptides are derived from pathogens, an immune response is initiated to eradicate the pathogen. In the small intestine of patients with CD, erroneous T cell responses are made against gluten peptides bound to HLA-DQ2 and/or-DQ8 [6–9], as if they were pathogen derived, producing large amounts of interferon-gamma, which is a mediator of inflammation. However, it was previously unclear how HLA-DQ2 and HLA-DQ8 bind gluten peptides. These molecules prefer peptides containing one or more negatively charged amino acids, yet gluten proteins are essentially devoid of these amino acids [10–12]. This paradox was resolved when it was observed that TG2 converts the glutamine residues in gluten peptides into glutamic acid, introducing the negative charges required for binding to …