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Glycosylation-directed quality control of protein folding

Key Points

  • Protein glycosylation describes various conserved post-translational modifications. Although some proteins can be glycosylated in the cytosol, glycosylation is most prevalent in the secretory pathway, in which it is involved in many processes.

  • Proteins that are synthesized at the endoplasmic reticulum (ER) membranes can be glycosylated at Asn, Ser and Thr residues. These can be further modified in the Golgi apparatus.

  • The core N-linked glycan has a branched structure composed of Glc3Man9GlcNAc2, which is trimmed sequentially by ER glycosidases. The trimming events coordinate folding and quality control factors to ensure high-fidelity production of mature glycoproteins.

  • Trimming of an N-linked glycan to the Man7GlcNAc2 structure bearing a terminal α-1,6-linked mannose residue attached to an unfolded peptide allows peptide recognition by the yeast osteosarcoma 9 (Yos9) ER-associated degradation (ERAD) receptor. This initiates peptide retro-translocation and degradation by the ubiquitin–proteasome system.

  • In budding yeast, misfolded proteins are modified by O-mannosylation by the Pmt1–Pmt2 complex. This modification can facilitate ERAD or promote the transport of the substrate out of the ER to the vacuole or cell surface.

  • O-mannosylation is used in budding yeast to terminate futile cycles of protein folding to facilitate their entry into ERAD and relieve ER stress.

Abstract

Membrane-bound and soluble proteins of the secretory pathway are commonly glycosylated in the endoplasmic reticulum. These adducts have many biological functions, including, notably, their contribution to the maturation of glycoproteins. N-linked glycans are of oligomeric structure, forming configurations that provide blueprints to precisely instruct the folding of protein substrates and the quality control systems that scrutinize it. O-linked mannoses are simpler in structure and were recently found to have distinct functions in protein quality control that do not require the complex structure of N-linked glycans. Together, recent studies reveal the breadth and sophistication of the roles of these glycan-directed modifications in protein biogenesis.

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Figure 1: Glycan precursors in the endoplasmic reticulum.
Figure 2: The Doa10 and HMG-CoA reductase degradation 1 (Hrd1) endoplasmic reticulum (ER)-associated degradation (ERAD) complexes and their downstream effectors.
Figure 3: N-linked glycan trimming in the endoplasmic reticulum (ER).
Figure 4: N-glycan directed protein folding and quality control.
Figure 5: The unfolded protein O-mannosylation pathway.

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Acknowledgements

The authors wish to express their sincere apologies to those researchers whose work is not cited owing to the scope of the review and space constraints, and thank Kun Yang for assistance in rendering figures. Work in the authors' laboratories is supported by funds from the Temasek Trust.

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Correspondence to Davis T. W. Ng.

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Glossary

HRD1 complex

Multi-subunit membrane protein complex in the endoplasmic reticulum (ER) that is organized around the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1). The HRD1 complex receives, retrotranslocates and ubiquitylates substrates for degradation by ER-associated degradation (ERAD).

Lectin

Member of a class of proteins that bind to carbohydrates. Lectins usually have high specificity for sugar type and/or glycan-linkage configuration.

Oxidoreductase

Member of a class of enzymes that mediate the transfer of electrons from one molecule to another. In the endoplasmic reticulum, most oxidoreductases form and break disulfide bonds.

Proteoliposomes

Particles composed of proteins and lipids, which are usually reconstituted from purified components.

DnaJ protein

A protein containing a 'J domain', which interacts with Hsp70 chaperones and stimulates their ATPase activity. Many DnaJ proteins are chaperones and directly bind to substrates.

Unfolded protein response

(UPR). A signalling response that is triggered by the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum.

Microsomes

Vesicles that are formed from endoplasmic reticulum membranes after mechanical cell disruption.

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Xu, C., Ng, D. Glycosylation-directed quality control of protein folding. Nat Rev Mol Cell Biol 16, 742–752 (2015). https://doi.org/10.1038/nrm4073

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