Terminally differentiating mammalian epidermal cells acquire an insoluble, 10 to 20 nm thick protein deposit on the intracellular surface of the plasma membrane, known as the cross-linked cell envelope (CE). The CE is a component of the epidermis that is generated through the formation of disulfide bonds and gamma-glutamyl-lysine isodipeptide bonds, which are formed by the action of transglutaminases (TGases). TGases are Ca2+-dependent enzymes, which catalyze the formation of isopeptide bonds by transferring an amine to a glutaminyl residue, thereby cross-linking glutamine residues and lysine residues in substrate proteins. TGases influence numerous biological processes, including blood coagulation, epidermal differentiation, seminal fluid coagulation, fertilization, cell differentiation and apoptosis. TGase6 (transglutaminase 6), also known as TGM6, TGY or TGM3L, is a 706 amino acid protein that catalyzes the cross-linking of proteins and the conjugation of proteins to polyamines. As a result of alternative splicing, two TGase6 isoforms exist.