Mammalian O-mannosylation of cadherins and plexins is independent of protein O-mannosyltransferases 1 and 2
- Ida Signe Bohse Larsen‡,
- Yoshiki Narimatsu‡,
- Hiren Jitendra Joshi‡,
- Zhang Yang‡,
- Oliver J. Harrison§,
- Julia Brasch§,
- Lawrence Shapiro§,¶,
- Barry Honig§,¶,‖,
- Sergey Y. Vakhrushev‡,
- Henrik Clausen‡ and
- Adnan Halim‡1
- From the ‡Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark, and
- the §Department of Biochemistry and Molecular Biophysics,
- ¶Zuckerman Mind Brain Behavior Institute, Department of Systems Biology, and
- ‖Howard Hughes Medical Institute Columbia University, New York, New York 10032
- ↵1 To whom correspondence should be addressed: Laboratory of Cellular and Structural Biology, The Rockefeller University, NY, New York 10065. E-mail: halim{at}sund.ku.dk.
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Edited by Gerald W. Hart
Abstract
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.
Footnotes
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This work was supported by A. P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til Almene For-maal, Kirsten og Freddy Johansen Fonden, The Carlsberg Foundation, The Novo Nordisk Foundation, The European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant 704228, The Danish Research Councils, National Science Foundation (NSF) Grant MCB-1412472 (to B. H.), National Institutes of Health Grants R01-GM10751 and R01GM118584 (to L. S.), the University of Copenhagen Program of Excellence, and the Danish National Research Foundation Grant DNRF107. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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This article contains supplemental Tables S1–S8.
- Received May 3, 2017.
- © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
