Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/112100
Title: Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling.
Author: Marada, Suresh
Navarro, Gemma
Truong, Ashley
Stewart, Daniel P
Arensdorf, Angela M
Nachtergaele, Sigrid
Angelats, Edgar
Opferman, Joseph T
Rohatgi, Rajat
McCormick, Peter J
Ogden, Stacey K
Keywords: Proteïnes de membrana
Proteïnes G
Vertebrats
Membrane proteins
G Proteins
Vertebrates
Issue Date: 20-Aug-2015
Publisher: Public Library of Science (PLoS)
Abstract: The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice.
Note: Reproducció del document publicat a: https://doi.org/10.1371/journal.pgen.1005473
It is part of: PLoS Genetics, 2015, vol. 11, num. 8, p. 1-27
Related resource: https://doi.org/10.1371/journal.pgen.1005473
URI: http://hdl.handle.net/2445/112100
ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)

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