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The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis

Nature Chemical Biology volume 10, pages 902–910 (2014)Cite this article

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Abstract

Proteins that traffic through the eukaryotic secretory pathway are commonly modified with N-linked carbohydrates. These bulky amphipathic modifications at asparagines intrinsically enhance solubility and folding energetics through carbohydrate-protein interactions. N-linked glycans can also extrinsically enhance glycoprotein folding by using the glycoprotein homeostasis or 'glycoproteostasis' network, which comprises numerous glycan binding and/or modification enzymes or proteins that synthesize, transfer, sculpt and use N-linked glycans to direct folding and trafficking versus degradation and trafficking of nascent N-glycoproteins through the cellular secretory pathway. If protein maturation is perturbed by misfolding, aggregation or both, stress pathways are often activated that result in transcriptional remodeling of the secretory pathway in an attempt to alleviate the insult (or insults). The inability to achieve glycoproteostasis is linked to several pathologies, including amyloidoses, cystic fibrosis and lysosomal storage diseases. Recent progress on genetic and pharmacologic adaptation of the glycoproteostasis network provides hope that drugs of this mechanistic class can be developed for these maladies in the near future.

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Figure 1: The initial composition of an N-linked glycan.
Figure 2: Intrinsic effects of N-glycosylation on protein folding.
Figure 3: N-linked glycans as protein sorting tags.
Figure 4: Calnexin post-translational modifications modulate ER localization.

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Acknowledgements

This work was supported by the National Institutes of Health under award numbers GM086874 and GM094848 (to D.N.H.); DK075295, AG046495 and GM051105 (to E.T.P. and J.W.K.); and a Chemistry-Biology Interface program training grant (GM08515 to L.L.).

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  1. Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts

    Daniel N Hebert & Lydia Lamriben

  2. Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA

    Evan T Powers & Jeffery W Kelly

  3. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

    Jeffery W Kelly

  4. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

    Jeffery W Kelly

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Hebert, D., Lamriben, L., Powers, E. et al. The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis. Nat Chem Biol 10, 902–910 (2014). https://doi.org/10.1038/nchembio.1651

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  • DOI: https://doi.org/10.1038/nchembio.1651

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