Tissue transglutaminase (TG2) is a multifunctional Ca2+ activated protein crosslinking enzyme secreted into the extracellular matrix (ECM), where it is involved in wound healing and scarring, tissue fibrosis, celiac disease and metastatic cancer. Extracellular TG2 can also facilitate cell adhesion important in wound healing through a non-transamidating mechanism via its association with fibronectin (FN), heparan sulphates (HS) and integrins. Regulating the mechanism how TG2 is translocated into the ECM therefore provides a strategy for modulating these physiological and pathological functions of the enzyme. Here, through molecular modelling and mutagenesis we have identified the HS binding site of TG2 202KFLKNAGRDCSRRSSPVYVGR222. We demonstrate the requirement of this binding site for translocation of TG2 into the ECM through a mechanism involving cell surface shedding of HS. By synthesizing a peptide NPKFLKNAGRDCSRRSS corresponding to the HS binding site within TG2, we also demonstrate how this mimicking peptide can in isolation compensate the RGD-induced loss of cell adhesion on FN via binding to syndecan-4, leading to activation of PKCa, pFAK-397 and ERK1/2 and the subsequent formation of focal adhesions and actin cytoskeleton organization. A novel regulatory mechanism for TG2 translocation into the extracellular compartment that depends upon TG2 conformation and the binding of HS is proposed.
Bibliographical noteThis research was originally published in the Journal of biological chemistry. Wang, Zhuo; Collighan, Russell; Pytel1, K; Rathbone, Dan L; Li, Xiaoling and Griffin, Martin Characterization of the heparin binding site of tissue transglutaminase: its importance in the enzyme’s cell surface targeting, matrix deposition and cell signalling. The Journal of biological chemistry. 2012; 13063-13083. © the American Society for Biochemistry and Molecular Biology
- tissue transglutaminase
- heparan sulphate
- extracellular matrix
Wang, Z., Collighan, R., Pytel, K., Rathbone, D. L., Li, X., & Griffin, M. (2012). Characterization of heparin-binding site of tissue transglutaminase: its importance in cell surface targeting, matrix deposition, and cell signaling. Journal of Biological Chemistry, 287(16), 13063-13083. https://doi.org/10.1074/jbc.M111.294819