Inter-molecular crosslinking activity is engendered by the dimeric form of transglutaminase 2

Kim, Nayeon; Lee, Won-Kyu; Lee, Seon-Hyeong; Jin, Kyeong Sik; Kim, Kyung‐Hee; Lee, Younho; Song, Minsoo; Kim, Soo-Youl

doi:10.1007/s00726-016-2293-1

Cited by 14 publications

(40 citation statements)

References 29 publications

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“…The acceleration of polymerization of TGase 2 has been observed by temperature increase only in the native PAGE (Kim et al 2017). This conformational change of purified recombinant TGase 2 affects size-exclusion chromatography (Kim et al 2017). TGase 2 triggers self-dimer formation from a monomeric state under 37 °C which is according to the previous report ( Fig.…”

Section: Gk921 Triggered Self-polymerization Of Tgase 2 Through Confosupporting

confidence: 73%

“…3a), which is not a covalently changed conformation because SDS PAGE showed no change of molecular weight size. The acceleration of polymerization of TGase 2 has been observed by temperature increase only in the native PAGE (Kim et al 2017). This conformational change of purified recombinant TGase 2 affects size-exclusion chromatography (Kim et al 2017).…”

Section: Gk921 Triggered Self-polymerization Of Tgase 2 Through Confomentioning

confidence: 96%

“…However, we did not find evidence how GK921 inhibits TGase 2 because GK921 does not have a warhead of attacking cysteine active site of TGase 2. The best answer is the co-crystallization of TGase 2 with GK921, but it is unable to obtain the suitable experimental results in a complexed situation due to folded or unfolded form of TGase 2 (Pinkas et al 2007) as well as due to monomeric or dimeric formation by temperature dependence (Kim et al 2017). GK921 ( Fig.…”

Section: Gk921 Inhibited Tgase 2 Activity In Vitromentioning

confidence: 99%

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Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

et al. 2018

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Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1-139 a.a)-p53 complex to the autophagosome, through TGase 2 (472-687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81-116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53-TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81-116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.

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Section: Gk921 Triggered Self-polymerization Of Tgase 2 Through Confosupporting

confidence: 73%

Section: Gk921 Triggered Self-polymerization Of Tgase 2 Through Confomentioning

confidence: 96%

Section: Gk921 Inhibited Tgase 2 Activity In Vitromentioning

confidence: 99%

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Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

et al. 2018

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“…Crystallographic data show that an open conformation is associated with a calcium‐dependent TGase activity while a closed conformation binds GTP and inhibits transamidating activity . In addition, the TG2 homotypic associations through C‐terminal residues would be involved in different inter‐ and intra‐cross‐linking regulatory activities …”

Section: Introductionmentioning

confidence: 99%

Alternative RNA splicing of leucocyte tissue transglutaminase in coeliac disease

et al. 2018

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Tissue transglutaminase is a ubiquitous and multifunctional protein that contributes to several processes such as apoptosis/survival, efferocytosis, inflammation and tissue repairing under physiological and pathological conditions. Several activities can be associated with well-established functional domains; in addition, four RNA alternative splice variants have been described, characterized by sequence divergences and residues deletion at the C-terminal domains. Tissue transglutaminase is recognized as the central player in the physiopathology of coeliac disease (CD) mainly through calcium-dependent enzymatic activities. It can be hypothesized that differential regulation of tissue transglutaminase splice variants expression in persons with CD contributes to pathology by altering the protein functionality. We characterized the expression pattern of RNA alternative splice variants by RT-PCR in peripheral cells from patients with CD under free gluten diet adhesion; we considered inflammatory parameters and specific antibodies as markers of the stage of disease. We found significant higher expression of both the full length and the shortest C-truncated splice variants in leucocytes from patients with CD in comparison with healthy individuals. As tissue transglutaminase expression and canonical enzymatic activity are linked to inflammation, we studied the RNA expression of inflammatory cytokines in peripheral leucocytes of persons with CD in relation with splice variants expression; interestingly, we found that recently diagnosed patients showed significant correlation between both the full length and the shortest alternative spliced variants with IL-1 expression. Our results points that regulation of alternative splicing of tissue transglutaminase could account for the complex physiopathology of CD.

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“…Extracellular Ca 2+ binds to ECM proteins by electrostatic force [42] and augments their stability. Also, calcium is needed for crosslinking activity of enzymes as transglutaminase 2 [43,44]. Therefore, an increase in Ca 2+ could aid the fibrosis progression.…”

Section: Resultsmentioning

confidence: 99%

Differentiation of fibrotic liver tissue using laser-induced breakdown spectroscopy

Terán-Hinojosa¹,

Sobral²,

Sánchez‐Pérez³

et al. 2017

Biomed. Opt. Express

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Hepatic cirrhosis is a major cause of morbidity and mortality worldwide due to hepatitis C, alcoholism and fatty liver disease associated with obesity. Assessment of hepatic fibrosis relies in qualitative histological evaluation of biopsy samples. This method is timeconsuming and depends on the histopathologists' interpretation. In the last decades, noninvasive techniques were developed to detect and monitor hepatic fibrosis. Laser-induced breakdown spectroscopy (LIBS) is a good candidate for a real-time, independent and fast technique to diagnose hepatic fibrosis. In this work LIBS was employed to characterize rat liver tissues with different stages of fibrosis. Depth profiling measurements were carried out by using a nanosecond Nd:YAG laser operated at the fundamental wavelength and an echelle spectrometer coupled with an ICCD camera. Due to the soft nature of the samples, plasma conditions largely change between consecutives shots. Thus, a theoretically supported procedure to correct the spectral line intensities was implemented. This procedure allows the reduction of the intensities' dispersion from 67% to 12%. After the correction, the LIBS signal shows an enhancement in calcium intensity by a factor of three as the fibrosis progressed. Calcium is known to increase crosslinking of extracellular matrix proteins in the fibrous septa. Therefore, our result singles it out as a key participant in the hepatic fibrosis.

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Inter-molecular crosslinking activity is engendered by the dimeric form of transglutaminase 2

Cited by 14 publications

References 29 publications

Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

Alternative RNA splicing of leucocyte tissue transglutaminase in coeliac disease

Differentiation of fibrotic liver tissue using laser-induced breakdown spectroscopy

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