Polymorphism of transglutaminase 2: unusually low frequency of genomic variants with deficient functions

Abstract

Transglutaminase 2 (TG2) is a multifunctional member of an enzyme family: it modifies glutamine residues by cross-linking proteins and incorporating primary amines into them, has protein disulphide isomerase and protein kinase activities, mediates trans-membrane signal transduction and interactions between cell surface proteins and the extracellular matrix. These unusual multiple roles encoded into one polypeptide chain suggest that genomic variations in the TGM2 gene should be limited. Indeed, the available information in databases shows that unlike in the case of most other transglutaminases there are no common single nucleotide polymorphisms in exons of human TGM2. We collected data on and produced some of the rare genetic variants of TGM2 by site directed mutagenesis and found that some were less stable than the most abundant (wild type) enzyme variant and the majority had deficient transamidating activity. Further studies are required to clarify the pathologic significance of these rare TGM2 alleles in the human population.

Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death

“…68 Micro-RNA (miR-19) directly downregulates TG2 expression and enhances the invasion of colorectal cancer cells. 18 Finally, the SUMOylation of TG2 enhances its protein levels and activity by blocking the ubiquitination of (and thus stabilizing) TG2 protein. 69 …”

Novel method for extracting exosomes of hepatocellular carcinoma cells

“…TGM2 has very diverse functions, including roles in cell differentiation, apoptosis, adhesion, receptormediated endocytosis, cell movement, and cell migration. Notably, TGM2 has bidirectional roles in cellular apoptosis, and the specific functions of TGM2 in different cell types are dependent on various factors, such as the specific apoptotic pathways and types of stimuli that are involved, the subcellular localization of TGM2, and the conversions catalyzed by the various enzymatic activities of TGM2 [24][25][26][27] . TGM2 and annexin A2 do not contain signal peptides or transmembrane domains.…”

Genomic variants reveal differential evolutionary constraints on human transglutaminases and point towards unrecognized significance of transglutaminase 2

“…We noticed earlier in limited exome sequence data sets that the protein coding sequence of human TGM2 has the lowest variability when compared to other members of the transglutaminase family [ 16 ]. In the present study we analyzed large scale population genomics data in an effort to understand evolutionary forces that have shaped this family of enzymes in human populations.…”