POST-TRANSLATIONAL MODIFICATION BY GALNAC ON MANNOSYLATED GLYCOPROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The glycoprotein alpha-dystroglycan (DG) has been the focus of considerable attention for several reasons, being the best characterized example of O-mannosylation in vertebrates, the direct connection between the O-Man glycans and function in DG's role of connecting muscle cells to the extracellular matrix, and the linkage of aberrations in its glycosylation to disease. The central mucin domain bears both O-Man and O-GalNAc glycans in a largely preserved pattern of glycosylation. With the O-Man residues being installed first in the ER, we have been interested in identifying how this directs the subsequent modification with O-GalNAc in the Golgi. An important issue in the post-translational modification is the interplay of sites of O-mannosylation with members of the family of polypeptide GalNAc transferases capable of installing GalNAc. To address this, we are working with the laboratory of Dr. Kelly Ten Hagen at NIH in characterizing the action of pp-GalNAc transferases on peptides and O-Man glycopeptides from DG we have synthesized. The constructs have been designed using sequence specific modification data on DG from Lance Wells' lab at the CCRC. The project combines expertise in GalNAc transferase analysis in the Ten Hagen lab and synthetic and analytical capabilities at the CCRC.