The physiological function and mode of regulation of transglutaminases are being studied as to their role in the formation of the cornified cell envelope in terminally differentiated mucosal epithelial cells and in mucosal pellicle formation in the human oral cavity. In the stratum distendum of human buccal epithelium, terminally differentiated cells form a stable cornified cell envelope as a result of crosslinking of specific cellular proteins. Salivary proteins are crosslinked to these cells to form the salivary pellicle. This pellicle that is found to be present in several cellular layers of the stratum distendum may constitute a multi-cell layered protective barrier of the oral mucosa. A cDNA encoding the cytosolic zymogen, for epidermal transglutaminase E was isolated. The primary structure of the zymogen was deduced from the nucleotide sequences and by partial amino acid sequence determination. This zymogen shares 45-49% sequence identidy with other transglutaminases. There are four highly conserved sequence located in regions carboxyl-terminal to the active site. Expression of membrane-associated transglutaminase K and its variant mutant clones in E. Coli provided a means to determine that there is a highly conserved sequence of amino acids, residues 105-572 essential for enzyme activity. The observation of a several-fold increase in catalytic activity with the mutant enzyme that lacks an amino-terminal peptide, residues 1-57, suggests that this peptide domain regulates activation of the enzyme.