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Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2

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Abstract

Transglutaminase 2 (TG2) is a ubiquitously expressed member of an enzyme family catalyzing Ca2+-dependent transamidation of proteins. It is a multifunctional protein having several well-defined enzymatic (GTP binding and hydrolysis, protein disulfide isomerase, and protein kinase activities) and non-enzymatic (multiple interactions in protein scaffolds) functions. Unlike its enzymatic interactions, the significance of TG2’s non-enzymatic regulation of its activities has recently gained importance. In this review, we summarize all the partners that directly interact with TG2 in a non-enzymatic manner and analyze how these interactions could modulate the crosslinking activity and cellular functions of TG2 in different cell compartments. We have found that TG2 mostly acts as a scaffold to bridge various proteins, leading to different functional outcomes. We have also studied how specific structural features, such as intrinsically disordered regions and embedded short linear motifs contribute to multifunctionality of TG2. Conformational diversity of intrinsically disordered regions enables them to interact with multiple partners, which can result in different biological outcomes. Indeed, ID regions in TG2 were identified in functionally relevant locations, indicating that they could facilitate conformational transitions towards the catalytically competent form. We reason that these structural features contribute to modulating the physiological and pathological functions of TG2 and could provide a new direction for detecting unique regulatory partners. Additionally, we have assembled all known anti-TG2 antibodies and have discussed their significance as a toolbox for identifying and confirming novel TG2 regulatory functions.

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Acknowledgments

This work was supported by the Hungarian Scientific Research Fund (OTKA NK 105046], the New Hungary Development Plan via the TAMOP-4.2.2.A-11/1/KONV-2012-0023 “V´ED ELEM” project, European Union Framework Programme 7 TRANSCOM-IAPP 251506 and TRANSPATH ITN 289964. The support of the Momentum program (LP2012-41) of the Hungarian Academy of Sciences is gratefully acknowledged (M. F.). We thank Dr. Máte Demény for critical reading of this manuscript.

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Kanchan, K., Fuxreiter, M. & Fésüs, L. Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2. Cell. Mol. Life Sci. 72, 3009–3035 (2015). https://doi.org/10.1007/s00018-015-1909-z

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  • DOI: https://doi.org/10.1007/s00018-015-1909-z

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