title: A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase.
abstract: Human core 1 beta3-galactosyltransferase (C1beta3Gal-T) generates the core 1 O-glycan Galbeta1-3GalNAcalpha1-SerThr (T antigen), which is a precursor for many extended O-glycans in animal glycoproteins. We report here that C1beta3Gal-T activity requires expression of a molecular chaperone designated Cosmc (core 1 beta3-Gal-T-specific molecular chaperone). The human Cosmc gene is X-linked (Xq23), and its cDNA predicts a 318-aa transmembrane protein ( approximately 36.4 kDa) with type II membrane topology. The human lymphoblastoid T cell line Jurkat, which lacks C1beta3Gal-T activity and expresses the Tn antigen GalNAcalpha1-SerThr, contains a normal gene and mRNA encoding C1beta3Gal-T, but contains a mutated Cosmc with a deletion introducing a premature stop codon. Expression of Cosmc cDNA in Jurkat cells restored C1beta3Gal-T activity and T antigen expression. Without Cosmc, the C1beta3Gal-T is targeted to proteasomes. Expression of active C1beta3Gal-T in Hi-5 insect cells requires coexpression of Cosmc. Overexpression of active C1beta3Gal-T in mammalian cell lines also requires coexpression of Cosmc, indicating that endogenous Cosmc may be limiting. A small portion of C1beta3Gal-T copurifies with Cosmc from cell extracts, demonstrating physical association of the proteins. These results indicate that Cosmc acts as a specific molecular chaperone in assisting the foldingstability of C1beta3Gal-T. The identification of Cosmc, a uniquely specific molecular chaperone required for a glycosyltransferase expression in mammalian cells, may shed light on the molecular basis of acquired human diseases involving altered O-glycosylation, such as IgA nephropathy, Tn syndrome, Henoch-Schönlein purpura, and malignant transformation, all of which are associated with a deficiency of C1beta3Gal-T activity.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Tongzhong
authors.initials: T
authors.lastname: Ju
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
mesh_terms: D000595:Amino Acid Sequence; D005700:Galactosyltransferases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation
chemical_list: D018832:Molecular Chaperones; D005700:Galactosyltransferases; C076385:glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase