title: Differential dependence on N-glycosylation of anthrax toxin receptors CMG2 and TEM8.
abstract: ANTXR 1 and 2, also known as TEM8 and CMG2, are two type I membrane proteins, which have been extensively studied for their role as anthrax toxin receptors, but with a still elusive physiological function. Here we have analyzed the importance of N-glycosylation on folding, trafficking and ligand binding of these closely related proteins. We find that TEM8 has a stringent dependence on N-glycosylation. The presence of at least one glycan on each of its two extracellular domains, the vWA and Ig-like domains, is indeed necessary for efficient trafficking to the cell surface. In the absence of any N-linked glycans, TEM8 fails to fold correctly and is recognized by the ER quality control machinery. Expression of N-glycosylation mutants reveals that CMG2 is less vulnerable to sugar loss. The absence of N-linked glycans in one of the extracellular domains indeed has little impact on folding, trafficking or receptor function of the wild type protein expressed in tissue culture cells. N-glycans do, however, seem required in primary fibroblasts from human patients. Here, the presence of N-linked sugars increases the tolerance to mutations in cmg2 causing the rare genetic disease Hyaline Fibromatosis Syndrome. It thus appears that CMG2 glycosylation provides a buffer towards genetic variation by promoting folding of the protein in the ER lumen.
authors.affiliation: Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Friebe
authors.affiliation: Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Deuquet
authors.affiliation: Faculty of Life Sciences, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D001665:Binding Sites; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
chemical_list: C473287:ANTXR1 protein, human; C447150:ANTXR2 protein, human; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C030325:anthrax toxin