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Mammalian O-mannosylation of cadherins and plexins is independent of protein O-mannosyltransferases 1 and 2

Journal Article · · Journal of Biological Chemistry
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  1. Univ. of Copenhagen (Denmark). Copenhagen Center for Glycomics. Dept. of Cellular and Molecular Medicine. Faculty of Health Sciences
  2. Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics
  3. Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics. Zuckerman Mind Brain Behavior Inst. Dept. of Systems Biology
  4. Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics. Zuckerman Mind Brain Behavior Inst. Dept. of Systems Biology. Howard Hughes Medical Inst.
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Protein O-mannosylation is found in yeast and metazoans, and a family of conserved orthologous protein O-mannosyltransferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O-linked mannose (O-Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O-Man glycans. Deficiencies in enzymes catalyzing O-Man biosynthesis, including the two human protein O-mannosyltransferases, POMT1 and POMT2, underlie a subgroup of congenital muscular dystrophies designated α-dystroglycanopathies, because deficient O-Man glycosylation of α-dystroglycan disrupts laminin interaction with α-dystroglycan and the extracellular matrix. To explore the functions of O-Man glycans on cadherins and protocadherins, we used a combinatorial gene-editing strategy in multiple cell lines to evaluate the role of the two POMTs initiating O-Man glycosylation and the major enzyme elongating O-Man glycans, the protein O-mannose β-1,2-N-acetylglucosaminyltransferase, POMGnT1. Surprisingly, O-mannosylation of cadherins and protocadherins does not require POMT1 and/or POMT2 in contrast to α-dystroglycan, and moreover, the O-Man glycans on cadherins are not elongated. Thus, the classical and evolutionarily conserved POMT O-mannosylation pathway is essentially dedicated to α-dystroglycan and a few other proteins, whereas a novel O-mannosylation process in mammalian cells is predicted to serve the large cadherin superfamily and other proteins.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1406611
Journal Information:
Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 27 Vol. 292; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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The roles of dystroglycan in the nervous system: insights from animal models of muscular dystrophy journal December 2018
Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions journal June 2018
Incorporation of desmocollin‐2 into the plasma membrane requires N ‐glycosylation at multiple sites journal April 2019
Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor journal August 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
cadherin
dystroglycan
glycomics
glycosylation
proteomics