Crystal Structure of Transglutaminase 2 with GTP Complex and Amino Acid Sequence Evidence of Evolution of GTP Binding Site

Jang, Tae Ho; Lee, Dong Sup; Choi, Kihang; Jeong, Eui Man; Kim, In Gyu; Kim, Young Whan; Chun, Jung Nyeo; Jeon, Ju Hong; Park, Hyun Ho

doi:10.1371/journal.pone.0107005

Cited by 52 publications

(66 citation statements)

References 38 publications

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“…The two conformational states of TG2 can be separated and visualized by non-denaturing PAGE due to the considerable difference in the hydrodynamic radius between open and closed conformations. GDP-bound TG2 (closed conformation) (Liu et al 2002;Jang et al 2014) and…”

Section: Binding Of Tg2 To Fn Is Independent Of Tg2 Conformation Andmentioning

confidence: 99%

“…Binding of effectors can have dramatic effects on the structure of TG2, illustrated by crystallization of the enzyme in two distinct conformational states. In the structure of human TG2 with bound GDP or GTP, the enzyme adopts a "closed" conformation in which the two C-terminal domains are folded in and interact with the catalytic core domain (Liu et al 2002;Jang et al 2014). The structure of TG2 with a peptide inhibitor bound in the active site, on the other hand, reveals an "open" conformation in which the four globular domains are aligned to give an extended structure (Pinkas et al 2007).…”

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confidence: 99%

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Dissecting the interaction between transglutaminase 2 and fibronectin

et al. 2016

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In the extracellular environment, the enzyme transglutaminase 2 (TG2) is involved in cell-matrix interactions through association with the extracellular matrix protein, fibronectin (FN). The 45 kDa gelatin-binding domain of FN (45FN) is responsible for the binding to TG2. Previous studies have demonstrated that the FN-binding site of TG2 is located in the N-terminal domain of the enzyme although with conflicting results regarding the specific residues involved. Here we have mapped the FN interaction site of human TG2 by use of hydrogen/deuterium exchange coupled with mass spectrometry, and we confirm that the FN-binding site is located in the N-terminal domain of TG2. Furthermore, by combination of site-directed mutagenesis and surface plasmon resonance analysis we have identified the TG2 residues K30, R116 and H134 as crucial to maintain the high affinity interaction with FN. Mutation of all three residues simultaneously reduced binding to 45FN by more than 2000-fold. We also identified residues in the catalytic core domain of TG2 that contributed to FN binding, hence extending the binding interface between TG2 and FN. This study provides new insights into the high affinity interaction between TG2 and FN.

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Section: Binding Of Tg2 To Fn Is Independent Of Tg2 Conformation Andmentioning

confidence: 99%

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confidence: 99%

Dissecting the interaction between transglutaminase 2 and fibronectin

et al. 2016

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“…Crystal structures of the enzyme in a complex with GDP or GTP reveal a "closed" conformation, in which the two C-terminal β-barrel domains are folded in on the catalytic core domain and cover the active site (14,15). Conversely, when a peptide inhibitor was irreversibly attached to the active site cysteine, the enzyme adopted an "open" conformation, where the four structural domains were aligned to give an extended structure (16).…”

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confidence: 99%

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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“…For the design and development of specific inhibitors, as drug molecules, understanding of the exact structure of the active site and pathophysiology of this protein is important [21]. Till now crystal structures of the inactive form TG2 bound to GTP, ATP and with irreversible inhibitors is reported [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Sequence Analysis and Structural Characterization of Tissue Transglutaminase 2(tg2) by in Silico Approach

Madagi

Parvatikar

2017

Int J Pharm Pharm Sci

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Objective: TG2 is multifunctional protein. The up regulation leads into different pathological disorders. The objective of the present study was the prediction of a structural feature of TG2 (Tissue transglutaminase) protein with in silico approach. Methods:In this study, we have investigated the structural feature of TG2 by using various biological databases (uniprot, NCBI, Pfam) and online tools such as BLAST, PDBsum, protoparam tools. Results:The predicted structure of TG2 protein has shown that amino acid residues conserved throughout the sequence in selected mammals. During the course of evolution, mammalian TG2 protein is orthologus; human TG2 shares its characters with chimpanzee while mice and rat were closely related to each other. This protein was mainly cytosolic but also present in other cell organalles. It has four catalytic domains and three active sites with multiple metal binding domain specifically for calcium. The pI value was 5.11, GRAVY-0.283. The phosphorylation sites were present at serine and threonine. The structure was a monomer with 14 alpha helices and 9 sheets. Ramachandran plot showed about 98% residues in the favoured region. Conclusion:Collectively, these data suggest that the predicted TG2 protein may act as a good therapeutic target. Targeting phosphorylation sites may help in down regulation of TG2. The modelled protein can be used for further work.

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Crystal Structure of Transglutaminase 2 with GTP Complex and Amino Acid Sequence Evidence of Evolution of GTP Binding Site

Cited by 52 publications

References 38 publications

Dissecting the interaction between transglutaminase 2 and fibronectin

Dissecting the interaction between transglutaminase 2 and fibronectin

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

Sequence Analysis and Structural Characterization of Tissue Transglutaminase 2(tg2) by in Silico Approach

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