Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues

The proline-rich gamma -carboxyglutamic acid (Gla) proteins (PRGPs) 1 and 2 are the founding members of a family of vitamin K-dependent single-pass in tegral membrane proteins characterized by an extracellular amino terminal d omain of approximately 45 amino acids that is rich in Gla. The intracellula r carboxyl terminal region of these two proteins contains one or two copies of the sequence PPXY, a motif present in a variety of proteins involved in such diverse cellular functions as signal transduction, cell cycle progres sion, and protein turnover. In this report, we describe the cloning of the cDNAs for two additional human transmembrane Cia proteins (TMG) of 20-24 kD a named TMG3 and TMG4, These two proteins possess extracellular Gla domains with 13 or 9 potential Gla residues, respectively, followed by membrane-sp anning hydrophobic regions and cytoplasmic carboxyl terminal regions that c ontain PPXY motifs. This emerging family of integral membrane Gla proteins includes proline-rich Gla protein (PRGP) 1, PRGP2, TMG3, and TMG4, all of w hich are characterized by broad and variable distribution in both fetal and adult tissues. Members of this family can be grouped into two subclasses o n the basis of their gene organization and amino acid sequence. These obser vations suggest novel physiological functions for vitamin K beyond its know n role in the biosynthesis of proteins involved in blood coagulation and bo ne development. The identification and characterization of these proteins m ay allow a more complete understanding of the teratogenic consequences of e xposure in utero to vitamin K antagonists, such as warfarin-based anticoagu lants.