Abstract
The protein crosslinking enzyme tissue transglutaminase (tTG) is an acyltransferase which catalyzes transamidation reactions between two proteins, or between a protein and a polyamine. It is frequently overexpressed in several different types of human cancer cells, where it has been shown to contribute to their growth, survival, and invasiveness. tTG is capable of adopting two distinct conformational states: a protein crosslinking active (“open”) state, and a GTP-bound, crosslinking inactive (“closed”) state. We have previously shown that the ectopic expression of mutant forms of tTG, which constitutively adopt the open conformation, are toxic to cells. This raises the possibility that strategies directed toward causing tTG to maintain an open state could potentially provide a therapeutic benefit for cancers in which tTG is highly expressed. Here, we report the identification of a small molecule, TTGM 5826, which stabilizes the open conformation of tTG. Treatment of breast and brain cancer cell lines, as well as glioma stem cells, with this molecule broadly inhibits their transformed phenotypes. Thus, TTGM 5826 represents the lead compound for a new class of small molecules that promote the toxicity of cancer cells by stabilizing the open state of tTG.
Highlights
Protein-glutamine γ-glutamyltransferase 2, more commonly referred to as tissue transglutaminase or type2 transglutaminase, is a member of the transglutaminase family of proteins
TTGM 5826 was predicted during the docking simulations to bind to the crosslinking active site of tissue transglutaminase (tTG) (Figure 2B), and we found that it exhibits a competitive inhibition versus the substrate NNDC (Figure 3C and 3D)
It seems likely that the majority of intracellular tTG in cancer cells exists in a closed state conformation, the ability to use MDC as a tTG substrate to label tTG glutamine-donors with a fluorescent dansyl group suggests that there is at least a basal level of tTG crosslinking activity [50, 58, 59]
Summary
Protein-glutamine γ-glutamyltransferase 2, more commonly referred to as tissue transglutaminase or type transglutaminase (tTG, EC = 2.3.2.13), is a member of the transglutaminase family of proteins. These proteins catalyze the crosslinking of a variety of substrates, in which a glutamine residue of one polypeptide chain is covalently linked to either the lysine of another peptide sequence, or to a non-peptidic amine-bearing small molecule, resulting in the formation of an amide bond and the release of ammonia [1]. A good deal of effort has been directed toward examining the roles played by tTG when it is released by cancer cells into the extracellular environment via non-classical secretory vesicles called microvesicles. The protein crosslinking activity of the microvesicle-associated tTG was shown to promote the ability of these vesicles to activate signaling www.oncotarget.com pathways in target cells that increased their growth and survival [8, 9]
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