Crystal structure of human transglutaminase 2 in complex with adenosine triphosphate

Han, Byeong-Gu; Cho, Jea-Won; Cho, Young Doo; Jeong, Kyung‐Chae; Kim, Soo-Youl; Lee, Byung Il

doi:10.1016/j.ijbiomac.2010.04.023

Cited by 59 publications

(58 citation statements)

References 24 publications

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“…The latter observation suggests that the enzyme is inactivated by oxidation in the extracellular environment. In this regard, Cys370 in TG2 has been implicated in disulfide bond formation with its neighbor Cys371 or, alternatively, with Cys230 (16,17,35). Based on the disappearance of signals from the mass spectrum of TG2 following oxidation, we could confirm the formation of these disulfide bonds.…”

Section: Discussionmentioning

confidence: 83%

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

Iversen

Mysling

Hnida

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The multifunctional enzyme transglutaminase 2 (TG2) is the target of autoantibodies in the gluten-sensitive enteropathy celiac disease. In addition, the enzyme is responsible for deamidation of gluten peptides, which are subsequently targeted by T cells. To understand the regulation of TG2 activity and the enzyme's role as an autoantigen in celiac disease, we have addressed structural properties of TG2 in solution by using hydrogen/deuterium exchange monitored by mass spectrometry. We demonstrate that Ca 2+ binding, which is necessary for TG2 activity, induces structural changes in the catalytic core domain of the enzyme. Cysteine oxidation was found to abolish these changes, suggesting a mechanism whereby disulfide bond formation inactivates the enzyme. Further, by using TG2-specific human monoclonal antibodies generated from intestinal plasma cells of celiac disease patients, we observed that binding of TG2 by autoantibodies can induce structural changes that could be relevant for the pathogenesis. Detailed mapping of two of the main epitopes targeted by celiac disease autoantibodies revealed that they are located adjacent to each other in the N-terminal part of the TG2 molecule.

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Section: Discussionmentioning

confidence: 83%

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

Iversen

Mysling

Hnida

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The 3-dimensional structure of TG2 has provided valuable insight into its function (9,23,24). The arrangement of amino acids within the active site has elucidated the catalytic machinery by which the enzyme does transamidation.…”

Section: Discussionmentioning

confidence: 99%

Targeting Ovarian Tumor Cell Adhesion Mediated by Tissue Transglutaminase

Khanna

Chelladurai

Gavini

et al. 2011

Molecular Cancer Therapeutics

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Tissue transglutaminase (TG2) is a transpeptidase involved in protein cross-linking through generation of e-(g-glutamyl)lysine isopeptide bonds. It also promotes cell adhesion through interaction with fibronectin and facilitates formation of fibronectin-integrin complexes. This interaction is involved in tumor cell adhesion to the matrix and in the process of tumor dissemination. Its inhibition by small molecules may therefore be useful in blocking metastasis. To that end, we screened more than 800,000 compounds following an in silico docking approach targeting two distinct cavities in the vicinity of the fibronectin-binding site on TG2. A total of 120 compounds were acquired and tested in cell culture-based assays for inhibition of ovarian tumor cell adhesion and proliferation. Seven compounds showed more than 50% inhibition of cell adhesion at a concentration of 25 mmol/L. A follow-up fluorescence polarization study revealed that one compound in particular (ITP-79) inhibited binding of a TG2 peptide to a 42-kDa fragment of fibronectin in a dose-dependent manner. This inhibition was confirmed in cancer cells by coimmunoprecipitation. A competition assay with surface plasmon resonance showed that ITP-79 modulated binding of TG2 to fibronectin. Direct binding of compounds that inhibited adhesion to TG2 were examined with differential scanning fluorimetry, which measures the effect of the compound on the melting temperature of the target. Two compounds, including ITP-79, reduced TG2 stabilization, mimicking the effects of GTP, a known negative allosteric regulator of TG2 enzymatic function. This suggests a potential allosteric mechanism for the compound in light of its distal target site. Mol Cancer Ther; 10(4); 626-36. Ó2011 AACR.

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“…2) based on the crystal structure of human factor XIII, another member of the TG family [13]. Also, its crystal structure is known in the GDP-bound [14] and ATP-bound [15] forms, as well as in an inhibitor-bound form, using Ac-P(DON)LPF-NH 2 , an irreversible inhibitor of human TG2 that binds to the active-site Cys residue [16]. These studies have revealed that TG2 is a monomeric protein that is composed of four domains: an NH 2 -terminal β-sandwich domain (residues 1-139); a transamidation catalytic core domain (residues 140-454), and two COOH-terminal β-barrel domains (residues 479-585 and 586-687).…”

Section: Tg2 and Its Role In Vascular Remodelingmentioning

confidence: 99%

“…However, different disulfide bonds were found to be present in two TG2 crystal structures. In the closed, ATP-bound molecule, a disulfide bridge between Cys 230 and Cys 370 is present [15], while in the open, inhibitor [Ac-P(DON)LPF-NH 2 ]-bound protein there is a bond between Cys 370 and Cys 371 [16]. These results seemed to imply that the two bonds between these Cys residues act as a switch for the redox regulation of TG2 activity, in which the Cys 230 -Cys 370 disulfide bond inhibits the activity and the Cys 370 -Cys 371 bond enhances it.…”

Section: Regulation Of Tg2 Activitymentioning

confidence: 99%

Activation of Extracellular Transglutaminase 2 by Mechanical Force in the Arterial Wall

et al. 2013

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Inward remodeling of small arteries occurs after prolonged vasoconstriction, low blood flow, and in several models of hypertension. The cross-linking enzyme, transglutaminases 2 (TG2), is able to induce inward remodeling and stiffening of arteries. The activity of TG2 is dependent on its conformation, which can be open or closed, and on its redox state. Several factors have been shown to be involved in modulating TG2 activity, including Ca²⁺ and GTP/GDP concentrations, as well as the redox state of the environment. This review introduces the hypothesis that mechanical force could be involved in regulating the activity of TG2 during inward remodeling by promoting its open and reduced active state. Several aspects of TG2, such as its structure and localization, are assessed in order to provide arguments that support the hypothesis. We conclude that a direct activation of TG2 by mechanical force exerted by smooth muscle cells may explain the link between smooth muscle activation and inward remodeling, as observed in several physiological and pathological conditions.

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Crystal structure of human transglutaminase 2 in complex with adenosine triphosphate

Cited by 59 publications

References 24 publications

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange

Targeting Ovarian Tumor Cell Adhesion Mediated by Tissue Transglutaminase

Activation of Extracellular Transglutaminase 2 by Mechanical Force in the Arterial Wall

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