γ-Glutamyl Carboxylation: An Extracellular Posttranslational Modification That Antedates the Divergence of Molluscs, Arthropods, and Chordates

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 3; pp. 1264 - 1269
• Main Authors: Bandyopadhyay, Pradip K., Garrett, James E., Shetty, Reshma P., Keate, Tyler, Walker, Craig S., Olivera, Baldomero M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.02.2002; National Acad Sciences; The National Academy of Sciences
• Series: From the Cover
• Subjects: Amino Acid Sequence; Amino acids; Animals; Arthropods; Biological Sciences; Brackish; Carbon-Carbon Ligases - chemistry; Carbon-Carbon Ligases - genetics; Carbon-Carbon Ligases - metabolism; Chordata, Nonvertebrate; Cloning, Molecular; Complementary DNA; Conus; Drosophila; Enzyme substrates; Enzymes; Exons; Freshwater; gamma -glutamyl carboxylase; Genomics; Humans; Introns; Mammalia; Marine; Molecular Sequence Data; Mollusca; Protein Processing, Post-Translational; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Snails; Textiles; Vertebrata; Vitamin K
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.022637099

The posttranslational γ-carboxylation of glutamate residues in secreted proteins to γ-carboxyglutamate is carried out by the vitamin K-dependent enzyme γ-glutamyl carboxylase. γ-Carboxylation has long been thought to be a biochemical specialization of vertebrates, essential for blood clotting. Recently, a γ-carboxylase was shown to be expressed in Drosophila, although its function remains undefined in this organism. We have characterized both cDNA and genomic clones for the γ-glutamyl carboxylase from the marine mollusc, Conus, the only nonvertebrate organism for which γ-carboxyglutamate-containing proteins have been biochemically and physiologically characterized. The predicted amino acid sequence has a high degree of sequence similarity to the Drosophila and vertebrate enzymes. Although γ-carboxylases are highly conserved, the Conus and mammalian enzymes have divergent substrate specificity. There are striking parallels in the gene organization of Conus and human γ-carboxylases. Of the 10 Conus introns identified, 8 are in precisely the same position as the corresponding introns in the human enzyme. This remarkable conservation of intron/exon boundaries reveals that an intron-rich γ-carboxylase was present early in the evolution of the animal phyla; although specialized adaptations in mammals and molluscs that require this extracellular modification have been identified, the ancestral function(s) and wider biological roles of γ-carboxylation still need to be defined. The data raise the possibility that most introns in the genes of both mammals and molluscs antedate the divergence of these phyla.