Functional significance of five noncanonical Ca2+‐binding sites of human transglutaminase 2 characterized by site‐directed mutagenesis

@article{Kirly2009FunctionalSO,
  title={Functional significance of five noncanonical Ca2+‐binding sites of human transglutaminase 2 characterized by site‐directed mutagenesis},
  author={R{\'o}bert Kir{\'a}ly and {\'E}va Csősz and Tibor Kurt{\'a}n and Sandor Dr Antus and Kriszti{\'a}n Szigeti and Zs{\'o}fia Simon-Vecsei and Ilma R. Korponay-Szab{\'o} and Zsolt Keresztessy and L{\'a}szl{\'o} F{\'e}s{\"u}s},
  journal={The FEBS Journal},
  year={2009},
  volume={276}
}
The multifunctional tissue transglutaminase 2 (TG2) has a four‐domain structure with several Ca2+‐regulated biochemical activities, including transglutamylation and GTP hydrolysis. The structure of the Ca2+‐binding form of the human enzyme is not known, and its Ca2+‐binding sites have not been fully characterized. By mutagenesis, we have targeted its active site Cys, three sites based on homology to Ca2+‐binding residues of epidermal transglutaminase and factor XIIIa (S1–S3), and two regions… Expand
Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+‐dependent action of a multifunctional protein
TLDR
A critical review of the experimental evidence supporting the role of this enzymatic activity in cellular processes is provided, which includes the structural basis of TG2 regulation through non‐canonical Ca2+ binding sites, mechanisms making it sensitive to lowCa2+ concentrations, techniques developed for the detection of protein transamidation in cells and examples of basic cellular phenomena as well as pathological conditions influenced by this irreversible post‐translational protein modification. Expand
Identification of a specific one amino acid change in recombinant human transglutaminase 2 that regulates its activity and calcium sensitivity.
TLDR
It is suggested that Val224 increases TG2 activity by modulating its calcium-binding affinity enabling transamidation reactions inside cells, andStructural analysis indicated a higher stability for TG2 valine residues and a decrease in flexibility of the calcium- binding loop resulting in improved metal- binding affinity. Expand
Competitive Binding of Magnesium to Calcium Binding Sites Reciprocally Regulates Transamidase and GTP Hydrolysis Activity of Transglutaminase 2
TLDR
Results indicate that E437 and E539 are Ca2+-binding sites contributing to the reciprocal regulation of transamidase and GTP binding/hydrolysis activities of TG2 through competitive Mg2+ binding. Expand
Isopeptidase activity of human transglutaminase 2: disconnection from transamidation and characterization by kinetic parameters
TLDR
The W278F mutation resulted in six times elevated amine incorporating transamidase activity demonstrating the regulatory significance of W278 and W332 in TG2 and that mutations can change opposed activities located at the same active site. Expand
An Unusual "OR" Gate for Allosteric Regulation of Mammalian Transglutaminase 2 in the Extracellular Matrix.
TLDR
It is demonstrated that extracellular TG2 activity is competitively controlled by the mutually exclusive binding of a high-affinity Ca2+ ion or the formation of a strained disulfide bond. Expand
Nucleotide binding kinetics and conformational change analysis of tissue transglutaminase with switchSENSE.
TLDR
This work shows how the combination of structural and kinetic information obtained by switchSENSE opens new perspectives for the characterization of conformationally active proteins and their interactions with ligands, e.g. potential drug candidates. Expand
Computational analyses of the effect of novel amino acid clusters of human transglutaminase 2 on its structure and function
TLDR
Comparative genomic and computational analysis reported here have revealed phylogenetic changes of TGM2 resulting in novel amino acid clusters in humans and other primates, which may impact secondary structure and increase protein stability. Expand
Factors important to the secretion and matrix deposition of tissue transglutaminase
TLDR
The findings indicate that the closed conformation of the enzyme as well as intact N-terminal tail and a novel HS binding site within the TG2 molecule are key elements for the enzyme’s localisation at the cell surface and its deposition into the extracellular matrix. Expand
Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2
TLDR
All the partners that directly interact with TG2 in a non-enzymatic manner are summarized and analyzed and it is found that TG2 mostly acts as a scaffold to bridge various proteins, leading to different functional outcomes. Expand
Activity-regulating structural changes and autoantibody epitopes in transglutaminase 2 assessed by hydrogen/deuterium exchange
TLDR
It is demonstrated that Ca2+ binding, which is necessary for TG2 activity, induces structural changes in the catalytic core domain of the enzyme, suggesting a mechanism whereby disulfide bond formation inactivates the enzyme. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 53 REFERENCES
Three‐dimensional structure of the human transglutaminase 3 enzyme: binding of calcium ions changes structure for activation
Transglutaminase (TGase) enzymes catalyze the formation of covalent cross‐links between protein‐bound glutamines and lysines in a calcium‐dependent manner, but the role of Ca2+ ions remains unclear.Expand
Mutation of a Critical Arginine in the GTP-binding Site of Transglutaminase 2 Disinhibits Intracellular Cross-linking Activity*
TLDR
Findings are consistent with the notion that intracellularly, under physiological conditions, TG2 is maintained largely as a latent enzyme, its calcium-activated cross-linking activity being suppressed allosterically by guanine nucleotide binding. Expand
Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity
  • S. Liu, R. Cerione, J. Clardy
  • Medicine, Biology
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The structure suggests a structural basis for the negative regulation of transamidation activity by bound nucleotide, and the positive regulation oftransamidation by Ca2+. Expand
Roles of Calcium Ions in the Activation and Activity of the Transglutaminase 3 Enzyme*
TLDR
Three more forms of the transglutaminase 3 enzyme are solved by x-ray crystallography in the presence of Ca2+ and/or Mg2+, which provide new insights on the precise contribution of eachCa2+ ion to activation and activity. Expand
Calcium Binding of Transglutaminases: A 43Ca NMR Study Combined with Surface Polarity Analysis
TLDR
Surface polarity analysis combined with multiple sequence alignment and the construction of a new homology model of human tissue transglutaminase suggested the existence of low affinity Ca2+ binding sites on both FXIII-A and tTGase in addition to high affinity ones in accordance with the surfacePolarity analysis identifying high numbers of negatively charged clusters. Expand
Site-directed mutagenesis of human tissue transglutaminase: Cys-277 is essential for transglutaminase activity but not for GTPase activity.
TLDR
Results demonstrate that Cys-277 is essential for transglutaminase activity, but not for GTP enzyme activity, and that N-terminal blocking of tissue-type transglutsaminase is not critical for either transglUTaminase or GTPase activities. Expand
Opposite Effects of Ca2+ and GTP Binding on Tissue Transglutaminase Tertiary Structure*
TLDR
It is found that calcium and GTP induced opposite conformational changes at the level of the protein tertiary structure, suggesting that the molecular mechanism by which tTG activity is inhibited by GTP is essentially due to a protein conformational change which, decreasing the accessibility of theprotein matrix to the solvent, renders more difficult the exposure of the active site. Expand
Site-directed mutation in conserved anionic regions of guinea pig liver transglutaminase.
TLDR
The results indicated that the negative charges of some acidic amino acid residues in the two conserved anionic regions of transglutaminase are not essential for its activity but the loss of their negative charges affects some catalytic properties. Expand
Transglutaminase 2 Undergoes a Large Conformational Change upon Activation
TLDR
The results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients. Expand
C-terminal Deletion of Human Tissue Transglutaminase Enhances Magnesium-dependent GTP/ATPase Activity*
TLDR
The C terminus functions to inhibit the expression of endogenous GTP/ATPase activity of tTG, and the potential role of the C termini in modulating this activity is discussed. Expand
...
1
2
3
4
5
...