Steinert PM. A magic size for the hierarchical structure of the human being epidermal cornified cell envelope. proteins by introducing covalent bonds between free amine organizations (e.g., protein- or peptide-bound lysine) and -carboxamide groups of peptide-bound Lestaurtinib glutamines (Number 1). Researchers recognized the 1st TG, now designated TG2, in 1959 from guinea pig liver extracts based on its ability to catalyze incorporation of low-molecular-weight main amines into proteins (306). Since the finding of TG2, additional proteins with this activity have been recognized from unicellular organisms, invertebrates, fish, mammals, and vegetation (122). Nine TG genes are present in humans. Eight are catalytically active enzymes, and the first is inactive (erythrocyte membrane protein band 4.2) (122). These proteins serve as scaffolds, maintain membrane integrity, regulate cell adhesion, and modulate transmission transduction (Table 1) (308). Although the primary sequence of the TGs differ, with the exception of band 4.2, all share an identical amino acid sequence in the active site (Number 2). In addition to the protein crosslinking and scaffolding functions, TGs catalyze posttranslational changes of proteins via deamidation and amine incorporation (Number 1). For example, TG2-dependent deamidation of gliadin A, a component of wheat and additional cereals, is definitely implicated in the pathogenesis of celiac disease (189). Similarly, deamidation of Gln63 in RhoA activates this signaling protein (108). Moreover, TG-catalyzed incorporation of amines into proteins can improve the function, stability, and immunogenicity of substrate proteins and contribute to autoimmune disease (220). Of the nine TGs recognized in humans, TG2 is the most widely distributed and most extensively analyzed. With this review, we describe the part of TGs in general, and TG2 in particular, and also explore the consequences of aberrant TG manifestation and activation. Table 1 summarizes the general features of each member of the TG family. Open in a separate window Number 1. Enzymatic reactions catalyzed by transglutaminases (TGs). Transamidation crosslinking reactions Lestaurtinib require the presence of Ca2+ to covalently link main amines including polyamines, monoamines, and protein-bound amines (P2) to a glutamine residue of the acceptor protein (P1). These reactions form polyamines or monoamine crosslinks with proteins (gene promoter consists of three activator protein Rabbit polyclonal to VASP.Vasodilator-stimulated phosphoprotein (VASP) is a member of the Ena-VASP protein family.Ena-VASP family members contain an EHV1 N-terminal domain that binds proteins containing E/DFPPPPXD/E motifs and targets Ena-VASP proteins to focal adhesions. AP2-like response elements located 0.5 kb from your transcription initiation site (238). Proteolytic cleavage, improved Ca2+ level, and connection with tazarotene-induced gene 3 (TIG3) are known to activate TG1 catalytic activity Lestaurtinib (98, 156, 331, 332). Phorbol esters induce and retinoic acid reduces mRNA and protein manifestation (97). TG1 protein associates with the plasma membrane via fatty acyl linkage in the NH2-terminal cysteine residue and is released by proteolysis as 10-, 33-, and 66-kDa fragments (183). Autosomal recessive lamellar ichthyosis results from mutation of the TG1-encoding gene (46, 71, 140, 141). Common mutations include a C-to-T switch in the binding site for the transcription element Sp1 within the promoter region, a Gly143-to-Glu mutation in exon 3, and a Val382-to-Met mutation in exon 7. Lamellar ichthyosis is definitely a rare keratinization disorder of the skin characterized by irregular cornification of the epidermis. Individuals with ichthyosis show drastically reduced TG1 activity and absence of detectable TG1 protein (46, 71, 140, 141). knockout mice show the lamellar ichthyosis phenotype Lestaurtinib (234). B. Transglutaminase 2 Cells TG (TG2), also referred to as TGc or Gh, is definitely widely distributed in cells and cell types. TG2 is mainly a cytosolic protein but is also present in the nucleus and on the plasma membrane (220). The TG2 gene promoter consists of a retinoic acid response element (1.7 kb upstream of the initiation site), an interleukin (IL)-6 specific expression. In addition to the transamidation reaction, TG2 displays GTPase, ATPase, protein kinase, and protein disulfide isomerase (PDI) activity. It interacts with phopholipase C1, -integrins, fibronectin, osteonectin, RhoA, multilineage kinases, retinoblastoma protein, PTEN, and IB. TG2 dysfunction contributes to celiac disease, neurodegenerative disorders, and cataract formation. knockout mice have no phenotype but display delayed wound healing and poor response to stress. Also, fibroblasts derived from mice display altered attachment and motility (351). C. Transglutaminase 3 Transglutaminase 3 (TG3) or epidermal TG is present in hair follicles, epidermis, and mind. The TG3 gene (knockout mice show impaired hair development and reduced pores and skin barrier function (36, 162). D. Transglutaminase 4 Transglutaminase 4 (TG4) or prostate TG is present in the prostate gland, prostatic fluids, and seminal plasma (91, 122, 160, 386). An Sp1-binding site, located ?96 to ?87 bp upstream of the transcription initiation site, is critical for transcriptional regulation of the TG4 gene expression, and androgen treatment increases TG4 mRNA level in the human being prostate cancer cells. In rats, the enzyme participates in the formation of the copulatory plug in the female genital tract, and in masking the antigenicity of the male gamete. knockout.