Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Vertebrate protein glycosylation: diversity, synthesis and function

Key Points

  • Contemporary studies of protein glycosylation have revealed numerous examples in which glycan structures attached to proteins and lipids have essential roles in biological recognition events. Glycans have critical functions throughout the cell, from the cytosol and secretory compartments to the cell surface and the extracellular space.

  • Conserved contributions of N-glycan structures in chaperone interactions and protein quality control are initiated co-translationally via the distinctive catalytic mechanism of the oligosaccharyltransferase, and glycan processing continues throughout the dynamic collection of secretory compartments that lead to the cell surface.

  • The complex assortment of glycosylation enzymes comprises an intricate assembly line for glycan maturation from the ER through the Golgi. The localization, dynamics, interactions, regulation and substrate competition of these enzymes within the ER and Golgi remains an active area of study.

  • Of the many roles that glycans have at the cell surface, emerging paradigms have highlighted the importance of protein domain-specific glycosylation in facilitating or modulating biological recognition events.

  • Advances in high-throughput glycan structural analysis are beginning to provide novel insights into correlations with gene expression patterns for glycosylation machinery and genome-wide associations that define global regulation of glycan diversity.

  • The diversity of glycan structures clearly provides an additional level of information content in biological systems, but the challenge for the future lies in identifying how different biological contexts determine glycan encoded functions within the bewildering array of heterogeneous glycan structures.

Abstract

Protein glycosylation is a ubiquitous post-translational modification found in all domains of life. Despite their significant complexity in animal systems, glycan structures have crucial biological and physiological roles, from contributions in protein folding and quality control to involvement in a large number of biological recognition events. As a result, they impart an additional level of 'information content' to underlying polypeptide structures. Improvements in analytical methodologies for dissecting glycan structural diversity, along with recent developments in biochemical and genetic approaches for studying glycan biosynthesis and catabolism, have provided a greater understanding of the biological contributions of these complex structures in vertebrates.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Protein N-glycosylation and quality control of protein folding.
Figure 2: Control points for Golgi trafficking and cellular glycomic diversity.

References

  1. 1

    Varki, A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3, 97–130 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Haltiwanger, R. S. & Lowe, J. B. Role of glycosylation in development. Annu. Rev. Biochem. 73, 491–537 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Dennis, J. W., Lau, K. S., Demetriou, M. & Nabi, I. R. Adaptive regulation at the cell surface by N-glycosylation. Traffic 10, 1569–1578 (2009).

    Article  CAS  Google Scholar 

  4. 4

    Hoseki, J., Ushioda, R. & Nagata, K. Mechanism and components of endoplasmic reticulum-associated degradation. J. Biochem. 147, 19–25 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Kollmann, K. et al. Mannose phosphorylation in health and disease. Eur. J. Cell Biol. 89, 117–123 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Hart, G. W., Slawson, C., Ramirez-Correa, G. & Lagerlof, O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80, 825–858 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Cummings, R. D. The repertoire of glycan determinants in the human glycome. Mol. Biosyst. 5, 1087–1104 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Rothman, J. E. & Fine, R. E. Coated vesicles transport newly synthesized membrane glycoproteins from endoplasmic reticulum to plasma membrane in two successive stages. Proc. Natl Acad. Sci. USA 77, 780–784 (1980).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Roth, J. Protein N-glycosylation along the secretory pathway: relationship to organelle topography and function, protein quality control, and cell interactions. Chem. Rev. 102, 285–303 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Peanne, R. et al. Differential effects of lobe A and lobe B of the Conserved Oligomeric Golgi complex on the stability of β1,4-galactosyltransferase 1 and α2,6-sialyltransferase 1. Glycobiology 21, 864–876 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Nairn, A. V. & Moremen, K. W. in Handbook of Glycomics (eds Cummings, R. & Pierce, J.M.) 95–136 (Academic Press, 2009).

    Google Scholar 

  12. 12

    Nairn, A. V. et al. Regulation of glycan structures in animal tissues: transcript profiling of glycan-related genes. J. Biol. Chem. 283, 17298–17313 (2008). Presents transcript analysis paired with glycan structural data to identify correlations between glycan-related gene expression and glycan composition in mouse tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Spiro, R. G. Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds. Glycobiology 12, 43R–56R (2002).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Schachter, H. The joys of HexNAc. The synthesis and function of N- and O-glycan branches. Glycoconj. J. 17, 465–483 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Schachter, H. The 'yellow brick road' to branched complex N-glycans. Glycobiology 1, 453–461 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Zaia, J. Mass spectrometry and glycomics. Omics: J. Integrative Biol. 14, 401–418 (2010).

    CAS  Google Scholar 

  17. 17

    Apweiler, R., Hermjakob, H. & Sharon, N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim. Biophys. Acta 1473, 4–8 (1999).

    Article  CAS  Google Scholar 

  18. 18

    Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Lizak, C., Gerber, S., Numao, S., Aebi, M. & Locher, K. P. X-ray structure of a bacterial oligosaccharyltransferase. Nature 474, 350–355 (2011). Reports the first structure of an OST in complex with a peptide substrate and describes a proposed mechanism that is likely to extend to the eukaryotic enzyme.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Kelleher, D. J. & Gilmore, R. An evolving view of the eukaryotic oligosaccharyltransferase. Glycobiology 16, 47R–62R (2006).

    Article  CAS  Google Scholar 

  21. 21

    Zielinska, D. F., Gnad, F., Wisniewski, J. R. & Mann, M. Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints. Cell 141, 897–907 (2010). Describes the use of lectin-affinity enrichment of glycopeptides followed by proteomics analysis to identify 6,367 mouse glycosylation sites, including several classes of novel acceptor sequons.

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Schreiner, R., Schnabel, E. & Wieland, F. Novel N-glycosylation in eukaryotes: laminin contains the linkage unit β-glucosylasparagine. J. Cell Biol. 124, 1071–1081 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Valliere-Douglass, J. F. et al. Glutamine-linked and non-consensus asparagine-linked oligosaccharides present in human recombinant antibodies define novel protein glycosylation motifs. J. Biol. Chem. 285, 16012–16022 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Kelleher, D. J., Karaoglu, D., Mandon, E. C. & Gilmore, R. Oligosaccharyltransferase isoforms that contain different catalytic STT3 subunits have distinct enzymatic properties. Mol. Cell 12, 101–111 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Imperiali, B. & Hendrickson, T. L. Asparagine-linked glycosylation: specificity and function of oligosaccharyl transferase. Bioorg. Med. Chem. 3, 1565–1578 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Larkin, A. & Imperiali, B. The expanding horizons of asparagine-linked glycosylation. Biochemistry 50, 4411–4426 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Schwarz, F. & Aebi, M. Mechanisms and principles of N-linked protein glycosylation. Curr. Opin. Struct. Biol. 21, 576–582 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Weerapana, E. & Imperiali, B. Asparagine-linked protein glycosylation: from eukaryotic to prokaryotic systems. Glycobiology 16, 91R–101R (2006).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Mohorko, E., Glockshuber, R. & Aebi, M. Oligosaccharyltransferase: the central enzyme of N-linked protein glycosylation. J. Inherit. Metab. Dis. 34, 869–878 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Helenius, A. & Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73, 1019–1049 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lederkremer, G. Z. Glycoprotein folding, quality control and ER-associated degradation. Curr. Opin. Struct. Biol. 19, 515–523 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    D'Alessio, C., Caramelo, J. J. & Parodi, A. J. UDP-GlC:glycoprotein glucosyltransferase-glucosidase II, the ying-yang of the ER quality control. Semin. Cell Dev. Biol. 21, 491–499 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Clerc, S. et al. Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J. Cell Biol. 184, 159–172 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Gauss, R., Kanehara, K., Carvalho, P., Ng, D. T. & Aebi, M. A complex of pdi1p and the mannosidase htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum. Mol. Cell 42, 782–793 (2011).

    Article  CAS  Google Scholar 

  35. 35

    Mast, S. W. & Moremen, K. W. Family 47 α-mannosidases in N-glycan processing. Methods Enzymol. 415, 31–46 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Moremen, K. W. & Molinari, M. N-linked glycan recognition and processing: the molecular basis of endoplasmic reticulum quality control. Curr. Opin. Struct. Biol. 16, 592–599 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Aebi, M., Bernasconi, R., Clerc, S. & Molinari, M. N-glycan structures: recognition and processing in the ER. Trends Biochem. Sci. 35, 74–82 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Xie, W., Kanehara, K., Sayeed, A. & Ng, D. T. Intrinsic conformational determinants signal protein misfolding to the Hrd1/Htm1 endoplasmic reticulum-associated degradation system. Mol. Biol. Cell 20, 3317–3329 (2009). Describes the roles of key N -linked glycan sites that mark structural determinants that are sensitive to the overall folding state of the molecule and mediate targeting of misfolded proteins for ER-associated degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kanehara, K., Xie, W. & Ng, D. T. Modularity of the Hrd1 ERAD complex underlies its diverse client range. J. Cell Biol. 188, 707–716 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    An, H. J. et al. Extensive determination of glycan heterogeneity reveals an unusual abundance of high mannose glycans in enriched plasma membranes of human embryonic stem cells. Mol. Cell. Proteomics 11, M111.010660 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Rabouille, C. et al. Mapping the distribution of Golgi enzymes involved in the construction of complex oligosaccharides. J. Cell Sci. 108, 1617–1627 (1995).

    CAS  PubMed  Google Scholar 

  42. 42

    Stanley, P. Golgi glycosylation. Cold Spring Harb. Perspect. Biol. 3, a005199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Mogelsvang, S., Marsh, B. J., Ladinsky, M. S. & Howell, K. E. Predicting function from structure: 3D structure studies of the mammalian Golgi complex. Traffic 5, 338–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Papanikou, E. & Glick, B. S. The yeast Golgi apparatus: insights and mysteries. FEBS Lett. 583, 3746–3751 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Ripoche, J., Link, B., Yucel, J. K., Tokuyasu, K. & Malhotra, V. Location of Golgi membranes with reference to dividing nuclei in syncytial Drosophila embryos. Proc. Natl Acad. Sci. USA 91, 1878–1882 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Velasco, A. et al. Cell type-dependent variations in the subcellular distribution of α-mannosidase I and II. J. Cell Biol. 122, 39–51 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Nilsson, T. et al. Overlapping distribution of two glycosyltransferases in the Golgi apparatus of HeLa cells. J. Cell Biol. 120, 5–13 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Chou, C. F. & Omary, M. B. Mitotic arrest with anti-microtubule agents or okadaic acid is associated with increased glycoprotein terminal GlcNAc's. J. Cell Sci. 107, 1833–1843 (1994).

    CAS  PubMed  Google Scholar 

  49. 49

    Haltiwanger, R. S. & Philipsberg, G. A. Mitotic arrest with nocodazole induces selective changes in the level of O-linked N-acetylglucosamine and accumulation of incompletely processed N-glycans on proteins from HT29 cells. J. Biol. Chem. 272, 8752–8758 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Klausner, R. D., Donaldson, J. G. & Lippincott-Schwartz, J. Brefeldin A: insights into the control of membrane traffic and organelle structure. J. Cell Biol. 116, 1071–1080 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Peyroche, A. et al. Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain. Mol. Cell 3, 275–285 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Rogalski, A. A., Bergmann, J. E. & Singer, S. J. Effect of microtubule assembly status on the intracellular processing and surface expression of an integral protein of the plasma membrane. J. Cell Biol. 99, 1101–1109 (1984).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Sampath, D., Varki, A. & Freeze, H. H. The spectrum of incomplete N-linked oligosaccharides synthesized by endothelial cells in the presence of brefeldin A. J. Biol. Chem. 267, 4440–4455 (1992).

    CAS  PubMed  Google Scholar 

  54. 54

    Balch, W. E., Dunphy, W. G., Braell, W. A. & Rothman, J. E. Reconstitution of the transport of protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine. Cell 39, 405–416 (1984).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Glick, B. S. & Luini, A. Models for Golgi traffic: a critical assessment. Cold Spring Harb. Perspect. Biol. 3, a005215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Goud, B. & Gleeson, P. A. TGN golgins, Rabs and cytoskeleton: regulating the Golgi trafficking highways. Trends Cell Biol. 20, 329–336 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Jackson, C. L. Mechanisms of transport through the Golgi complex. J. Cell Sci. 122, 443–452 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Jamieson, J. D. & Palade, G. E. Intracellular transport of secretory proteins in the pancreatic exocrine cell. 3. Dissociation of intracellular transport from protein synthesis. J. Cell Biol. 39, 580–588 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Kartberg, F., Elsner, M., Froderberg, L., Asp, L. & Nilsson, T. Commuting between Golgi cisternae--mind the GAP! Biochim. Biophys. Acta 1744, 351–363 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Marchi, F. & Leblond, C. P. Radioautographic characterization of successive compartments along the rough endoplasmic reticulum-Golgi pathway of collagen precursors in foot pad fibroblasts of [3H]proline-injected rats. J. Cell Biol. 98, 1705–1709 (1984).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Reynders, E., Foulquier, F., Annaert, W. & Matthijs, G. How Golgi glycosylation meets and needs trafficking: the case of the COG complex. Glycobiology 21, 853–863 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Munro, S. An investigation of the role of transmembrane domains in Golgi protein retention. EMBO J. 14, 4695–4704 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Patterson, G. H. et al. Transport through the Golgi apparatus by rapid partitioning within a two-phase membrane system. Cell 133, 1055–1067 (2008). Proposes a model for Golgi trafficking in which cargo proteins are not carried through the Golgi as if on a conveyer belt. Rather, cargo proteins partition into processing or transport domains that possess distinctive lipid compositions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Sharpe, H. J., Stevens, T. J. & Munro, S. A comprehensive comparison of transmembrane domains reveals organelle-specific properties. Cell 142, 158–169 (2010). A tour-de-force bioinformatic analysis of the physico-chemical properties of transmembrane domains of organellar proteins from fungi to vertebrates, demonstrating a conserved dichotomy in transmembrane domain properties that distinguish early from late secretory compartments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Schmitz, K. R. et al. Golgi localization of glycosyltransferases requires a Vps74p oligomer. Dev. Cell 14, 523–534 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Tu, L., Tai, W. C., Chen, L. & Banfield, D. K. Signal-mediated dynamic retention of glycosyltransferases in the Golgi. Science 321, 404–407 (2008).

    Article  CAS  Google Scholar 

  67. 67

    Aoki, D., Lee, N., Yamaguchi, N., Dubois, C. & Fukuda, M. N. Golgi retention of a trans-Golgi membrane protein, galactosyltransferase, requires cysteine and histidine residues within the membrane-anchoring domain. Proc. Natl Acad. Sci. USA 89, 4319–4323 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Colley, K. J. Golgi localization of glycosyltransferases: more questions than answers. Glycobiology 7, 1–13 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Colley, K. J., Lee, E. U. & Paulson, J. C. The signal anchor and stem regions of the β-galactoside α2,6-sialyltransferase may each act to localize the enzyme to the Golgi apparatus. J. Biol. Chem. 267, 7784–7793 (1992).

    CAS  PubMed  Google Scholar 

  70. 70

    Fenteany, F. H. & Colley, K. J. Multiple signals are required for α2,6-sialyltransferase (ST6Gal I) oligomerization and Golgi localization. J. Biol. Chem. 280, 5423–5429 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Nilsson, T., Lucocq, J. M., Mackay, D. & Warren, G. The membrane spanning domain of β-1,4-galactosyltransferase specifies trans Golgi localization. EMBO J. 10, 3567–3575 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Nilsson, T., Rabouille, C., Hui, N., Watson, R. & Warren, G. The role of the membrane-spanning domain and stalk region of N-acetylglucosaminyltransferase I in retention, kin recognition and structural maintenance of the Golgi apparatus in HeLa cells. J. Cell Sci. 109, 1975–1989 (1996).

    CAS  PubMed  Google Scholar 

  73. 73

    Banfield, D. K. Mechanisms of protein retention in the Golgi. Cold Spring Harb. Perspect. Biol. 3, a005264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Tu, L. & Banfield, D. K. Localization of Golgi-resident glycosyltransferases. Cell. Mol. Life Sci. 67, 29–41 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Nilsson, T., Slusarewicz, P., Hoe, M. H. & Warren, G. Kin recognition. A model for the retention of Golgi enzymes. FEBS Lett. 330, 1–4 (1993).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Hassinen, A., Rivinoja, A., Kauppila, A. & Kellokumpu, S. Golgi N-glycosyltransferases form both homo- and heterodimeric enzyme complexes in live cells. J. Biol. Chem. 285, 17771–17777 (2010). Bimolecular fluorescence complementation reveals that key glycosyltransferases form homocomplexes, but also form distinct heterocomplexes with functionally related glycosyltransferases that are localized to either medial or trans -Golgi compartments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Daniotti, J. L., Martina, J. A., Giraudo, C. G., Zurita, A. R. & Maccioni, H. J. GM3 α2,8-sialyltransferase (GD3 synthase): protein characterization and sub-golgi location in CHO-K1 cells. J. Neurochem. 74, 1711–1720 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Giraudo, C. G. & Maccioni, H. J. Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J. Biol. Chem. 278, 40262–40271 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Yano, H. et al. Distinct functional units of the Golgi complex in Drosophila cells. Proc. Natl Acad. Sci. USA 102, 13467–13472 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Freeze, H. H. Congenital disorders of glycosylation: CDG-I, CDG-II, and beyond. Curr. Mol. Med. 7, 389–396 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Foulquier, F. COG defects, birth and rise! Biochim. Biophys. Acta 1792, 896–902 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Pokrovskaya, I. D. et al. Conserved oligomeric Golgi complex specifically regulates the maintenance of Golgi glycosylation machinery. Glycobiology 21, 1554–1569 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Smith, R. D. & Lupashin, V. V. Role of the conserved oligomeric Golgi (COG) complex in protein glycosylation. Carbohydr. Res. 343, 2024–2031 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Wu, X. et al. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nature Med. 10, 518–523 (2004). First demonstration of a human disorder associated with altered Golgi transport. Patient fibroblasts were shown to be deficient in intra-Golgi transport.

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Oka, T., Ungar, D., Hughson, F. M. & Krieger, M. The COG and COPI complexes interact to control the abundance of GEARs, a subset of Golgi integral membrane proteins. Mol. Biol. Cell 15, 2423–2435 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Gill, D. J., Chia, J., Senewiratne, J. & Bard, F. Regulation of O-glycosylation through Golgi-to-ER relocation of initiation enzymes. J. Cell Biol. 189, 843–858 (2010). SRC-dependent growth factor stimulation drives the relocation of polypeptide GalNAc transferases to earlier secretory compartments, enhancing the production of GalNAc initiated O -linked glycans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Baas, S. et al. Sugar-free frosting, a homolog of SAD kinase, drives neural-specific glycan expression in the Drosophila embryo. Development 138, 553–563 (2011). A partial loss-of-function mutation in a neural specific kinase decreases expression of a set of neural-specific glycans, demonstrating a direct link between protein phosphorylation, Golgi architecture and glycan end-products.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Farhan, H. et al. MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening. J. Cell Biol. 189, 997–1011 (2010). An RNA interference screen for kinases and phosphatases that alter ER and Golgi trafficking identified 122 such proteins, indicating a broad role for cell signaling in sculpting flux through the secretory pathway with subsequent, but not yet demonstrated, glycomic consequences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Lowe, M. et al. Cdc2 kinase directly phosphorylates the cis-Golgi matrix protein GM130 and is required for Golgi fragmentation in mitosis. Cell 94, 783–793 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Muniz, M., Alonso, M., Hidalgo, J. & Velasco, A. A regulatory role for cAMP-dependent protein kinase in protein traffic along the exocytic route. J. Biol. Chem. 271, 30935–30941 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Colley, K. J. Structural basis for the polysialylation of the neural cell adhesion molecule. Adv. Exp. Med. Biol. 663, 111–126 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Rana, N. A. & Haltiwanger, R. S. Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Curr. Opin. Struct. Biol. 21, 583–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Hanisch, F. G. & Breloy, I. Protein-specific glycosylation: signal patches and cis-controlling peptidic elements. Biol. Chem. 390, 619–626 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Luther, K. B. & Haltiwanger, R. S. Role of unusual O-glycans in intercellular signaling. Int. J. Biochem. Cell Biol. 41, 1011–1024 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Muntoni, F., Torelli, S., Wells, D. J. & Brown, S. C. Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies. Curr. Opin. Neurol. 24, 437–442 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Stanley, P. & Okajima, T. Roles of glycosylation in Notch signaling. Curr. Top. Dev. Biol. 92, 131–164 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Wopereis, S., Lefeber, D. J., Morava, E. & Wevers, R. A. Mechanisms in protein O-glycan biosynthesis and clinical and molecular aspects of protein O-glycan biosynthesis defects: a review. Clin. Chem. 52, 574–600 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Sakaidani, Y. et al. O-linked-N-acetylglucosamine modification of mammalian Notch receptors by an atypical O-GlcNAc transferase Eogt1. Biochem. Biophys. Res. Commun. 419, 14–19 (2012). The authors identifyied a unique O -GlcNAc transferase, EOGT, involved in the O -GlcNAcylation of extracellular proteins.

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Shao, L., Moloney, D. J. & Haltiwanger, R. Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. J. Biol. Chem. 278, 7775–7782 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Wang, Y. et al. Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase. J. Biol. Chem. 276, 40338–40345 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Okajima, T. & Irvine, K. D. Regulation of Notch signaling by O-linked fucose. Cell 111, 893–904 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Shi, S. & Stanley, P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc. Natl Acad. Sci. USA 100, 5234–5239 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Yao, D. et al. Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood 117, 5652–5662 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Acar, M. et al. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132, 247–258 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Sethi, M. K. et al. Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated notch epidermal growth factor repeats. J. Biol. Chem. 285, 1582–1586 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Sethi, M. K. et al. Molecular cloning of a xylosyltransferase that transfers the second xylose to O-glucosylated epidermal growth factor repeats of notch. J. Biol. Chem. 287, 2739–2748 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Rana, N. A. et al. O-Glucose trisaccharide is present at high but variable stoichiometry at multiple sites on mouse Notch1. J. Biol. Chem. 286, 31623–31637 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Fernandez-Valdivia, R. et al. Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi. Development 138, 1925–1934 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Sakaidani, Y. et al. O-linked-N-acetylglucosamine on extracellular protein domains mediates epithelial cell-matrix interactions. Nature Commun. 2, 583 (2011).

    Article  CAS  Google Scholar 

  110. 110

    Matsuura, A. et al. O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. J. Biol. Chem. 283, 35486–35495 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Hofsteenge, J. et al. C-mannosylation and O-fucosylation of the thrombospondin type 1 module. J. Biol. Chem. 276, 6485–6498 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Luo, Y., Koles, K., Vorndam, W., Haltiwanger, R. S. & Panin, V. M. Protein O-fucosyltransferase 2 adds O-fucose to thrombospondin type 1 repeats. J. Biol. Chem. 281, 9393–9399 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Martinez-Duncker, I., Mollicone, R., Candelier, J. J., Breton, C. & Oriol, R. A new superfamily of protein-O-fucosyltransferases, α2-fucosyltransferases, and α6-fucosyltransferases: phylogeny and identification of conserved peptide motifs. Glycobiology 13, 1C–5C (2003).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Kozma, K. et al. Identification and characterization of a β1,3-glucosyltransferase that synthesizes the Glc-β1,3-Fuc disaccharide on thrombospondin type 1 repeats. J. Biol. Chem. 281, 36742–36751 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Sato, T. et al. Molecular cloning and characterization of a novel human β1,3-glucosyltransferase, which is localized at the endoplasmic reticulum and glucosylates O-linked fucosylglycan on thrombospondin type 1 repeat domain. Glycobiology 16, 1194–1206 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Ricketts, L. M., Dlugosz, M., Luther, K. B., Haltiwanger, R. S. & Majerus, E. M. O-fucosylation is required for ADAMTS13 secretion. J. Biol. Chem. 282, 17014–17023 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Du, J. et al. O-fucosylation of thrombospondin type 1 repeats restricts epithelial to mesenchymal transition (EMT) and maintains epiblast pluripotency during mouse gastrulation. Dev. Biol. 346, 25–38 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Doucey, M. A., Hess, D., Cacan, R. & Hofsteenge, J. Protein C-mannosylation is enzyme-catalysed and uses dolichyl-phosphate-mannose as a precursor. Mol. Biol. Cell 9, 291–300 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Krieg, J. et al. Recognition signal for C-mannosylation of Trp-7 in RNase 2 consists of sequence Trp-x-x-Trp. Mol. Biol. Cell 9, 301–309 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Wang, L. W., Leonhard-Melief, C., Haltiwanger, R. S. & Apte, S. S. Post-translational modification of thrombospondin type-1 repeats in ADAMTS-like 1/punctin-1 by C-mannosylation of tryptophan. J. Biol. Chem. 284, 30004–30015 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Barresi, R. & Campbell, K. P. Dystroglycan: from biosynthesis to pathogenesis of human disease. J. Cell Sci. 119, 199–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Stalnaker, S. H. et al. Glycomic analyses of mouse models of congenital muscular dystrophy. J. Biol. Chem. 286, 21180–21190 (2011). Analysis of O -linked glycans from brains of wild-type and knockout mouse models using mass spectrophotometry to determine that POMGNT1 is required for addition of β1,2-linked GlcNAc on O -Man glycans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Stalnaker, S. H. et al. Site mapping and characterization of O-glycan structures on α-dystroglycan isolated from rabbit skeletal muscle. J. Biol. Chem. 285, 24882–24891 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Combs, A. C. & Ervasti, J. M. Enhanced laminin binding by α-dystroglycan after enzymatic deglycosylation. Biochem. J. 390, 303–309 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Hara, Y. et al. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N. Engl. J. Med. 364, 939–946 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Yoshida-Moriguchi, T. et al. O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding. Science 327, 88–92 (2010). First description of a novel GAG-like structure containing Xyl and GlcA in unknown linkage to an essential extracellular protein that interacts with the extracellular matrix.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Inamori, K. et al. Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE. Science 335, 93–96 (2012). Reports the bifunctional glycosyltransferase activity of LARGE1 on O -Man-containing glycans of αDG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Zhang, Z., Zhang, P. & Hu, H. LARGE expression augments the glycosylation of glycoproteins in addition to α-dystroglycan conferring laminin binding. PLoS ONE 6, e19080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Nairn, A. V., dela Rosa, M. & Moremen, K. W. Transcript analysis of stem cells. Methods Enzymol. 479, 73–91 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Hua, S. et al. Comprehensive native glycan profiling with isomer separation and quantitation for the discovery of cancer biomarkers. Analyst 136, 3663–3671 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    An, H. J., Kronewitter, S. R., de Leoz, M. L. & Lebrilla, C. B. Glycomics and disease markers. Curr. Opin. Chem. Biol. 13, 601–607 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Bielik, A. M. & Zaia, J. Historical overview of glycoanalysis. Methods Mol. Biol. 600, 9–30 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Aoki, K. et al. The diversity of O-linked glycans expressed during Drosophila melanogaster development reflects stage- and tissue-specific requirements for cell signaling. J. Biol. Chem. 283, 30385–30400 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Haab, B. B. Antibody-lectin sandwich arrays for biomarker and glycobiology studies. Expert Rev. Proteom. 7, 9–11 (2010).

    Article  CAS  Google Scholar 

  135. 135

    Yue, T. et al. The prevalence and nature of glycan alterations on specific proteins in pancreatic cancer patients revealed using antibody-lectin sandwich arrays. Mol. Cell. Proteomics 8, 1697–1707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Li, C. et al. Pancreatic cancer serum detection using a lectin/glyco-antibody array method. J. Proteome Res. 8, 483–492 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Adamczyk, B., Tharmalingam, T. & Rudd, P. M. Glycans as cancer biomarkers. Biochim. Biophys. Acta 9 Dec 2011 (doi:10.1016/j.bbagen.2011.12.001).

  138. 138

    Lauc, G. et al. Genomics meets glycomics-the first GWAS study of human N-glycome identifies HNF1α as a master regulator of plasma protein fucosylation. PLoS Genet. 6, e1001256 (2010). Describes the first study that linked high-throughput glycan structural analysis and genome-wide association to identify determinants that control population-specific expression of carbohydrate epitopes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Huffman, J. E. et al. Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults. Hum. Mol. Genet. 20, 5000–5011 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Esko, J. D. & Selleck, S. B. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu. Rev. Biochem. 71, 435–471 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Wang, A., de la Motte, C., Lauer, M. & Hascall, V. Hyaluronan matrices in pathobiological processes. FEBS J. 278, 1412–1418 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Tian, E. & Ten Hagen, K. G. Recent insights into the biological roles of mucin-type O-glycosylation. Glycoconj. J. 26, 325–334 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Issoglio, F. M., Carrizo, M. E., Romero, J. M. & Curtino, J. A. Mechanisms of monomeric and dimeric glycogenin autoglucosylation. J. Biol. Chem. 287, 1955–1961 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Schegg, B., Hulsmeier, A. J., Rutschmann, C., Maag, C. & Hennet, T. Core glycosylation of collagen is initiated by two β(1-O)galactosyltransferases. Mol. Cell. Biol. 29, 943–952 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Pontier, S. M. & Schweisguth, F. Glycosphingolipids in signaling and development: from liposomes to model organisms. Dev. Dyn. 241, 92–106 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Farquhar, M. G. & Palade, G. E. The Golgi apparatus: 100 years of progress and controversy. Trends Cell Biol. 8, 2–10 (1998).

    Article  CAS  Google Scholar 

  147. 147

    Perry, R. J. & Ridgway, N. D. Molecular mechanisms and regulation of ceramide transport. Biochim. Biophys. Acta 1734, 220–234 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    van Meer, G. & de Kroon, A. I. Lipid map of the mammalian cell. J. Cell Sci. 124, 5–8 (2011).

    Article  CAS  Google Scholar 

  149. 149

    Smith, M. H., Ploegh, H. L. & Weissman, J. S. Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334, 1086–1090 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Seemann, J., Jokitalo, E., Pypaert, M. & Warren, G. Matrix proteins can generate the higher order architecture of the Golgi apparatus. Nature 407, 1022–1026 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. 151

    Slusarewicz, P., Nilsson, T., Hui, N., Watson, R. & Warren, G. Isolation of a matrix that binds medial Golgi enzymes. J. Cell Biol. 124, 405–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Ramirez, I. B. & Lowe, M. Golgins and GRASPs: holding the Golgi together. Semin. Cell Dev. Biol. 20, 770–779 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Maccioni, H. J., Quiroga, R. & Spessott, W. Organization of the synthesis of glycolipid oligosaccharides in the Golgi complex. FEBS Lett. 585, 1691–1698 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Gerken, T. A. et al. Emerging paradigms for the initiation of mucin-type protein O-glycosylation by the polypeptide GalNAc transferase family of glycosyltransferases. J. Biol. Chem. 286, 14493–14507 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Gupta, R. & Brunak, S. Prediction of glycosylation across the human proteome and the correlation to protein function. Pac. Symp. Biocomput. 2002, 310–322 (2002).

    Google Scholar 

  156. 156

    Roch, C., Kuhn, J., Kleesiek, K. & Gotting, C. Differences in gene expression of human xylosyltransferases and determination of acceptor specificities for various proteoglycans. Biochem. Biophys. Res. Commun. 391, 685–691 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. 157

    Manya, H. et al. Regulation of mammalian protein O-mannosylation: preferential amino acid sequence for O-mannose modification. J. Biol. Chem. 282, 20200–20206 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Pierleoni, A., Martelli, P. L. & Casadio, R. PredGPI: a GPI-anchor predictor. BMC Bioinformat. 9, 392 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants from the National Center for Research Resources (P41RR005351 and P41RR018502) and the National Institute of General Medical Sciences (P41GM103390 and P41GM103490) to J. Prestegard and J. M. Pierce and NIH grants R01GM047533 and R01DK075322 to K.W.M., as well as P01GM085354 and R01GM072839 to M.T.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kelley W. Moremen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Complex Carbohydrate Research Center at the University of Georgia

Carbohydrate-Active enZYmes Database

CFG Functional Glycomics Gateway

Essentials of Glycobiology, 2nd edn

Glycobiology journal

Integrated Technology Resource for Biomedical Glycomics

Society for Glycobiology

YinOYangWWW.server(neuralnetworkpredictionsforO-β-GlcNAcattachmentsites)

Glossary

Lectins

Carbohydrate binding proteins that are involved in various biological recognition phenomena.

Sialic acid

(SA; also known as neuraminic acid (Neu)). SAs are a family of nine-carbon monosaccharides with a carboxylic acid at the C1 position and a glycerol side chain at C7-C9. Two SAs predominate in vertebrates, with either an N-acetyl group (NeuAc) or an N-glycolyl group (NeuGc) at C5. Humans do not make NeuGc, but can obtain it from their diet and incorporate it into glycoconjugates.

Lipid-linked oligosaccharide

(LLO). Extended carbohydrate structure attached through a phosphodiester linkage to a polyisoprenoid lipid, usually dolichol. N-linked glycan precursor structures are commonly assembled as a lipid-linked intermediate before transfer to a polypeptide side chain.

Oligosaccharyltransferase

(OST). A multi-enzyme complex (or single subunit in bacteria) in the endoplasmic reticulum membrane that transfers glycan structures from a lipid-linked oligosaccharide precursor to acceptor sequences on nascent polypeptides.

Acceptor peptide sequons

Short amino acid sequences on glycan-acceptor polypeptide chains that are recognized by glycosyltransferases prior to glycosylation.

Calnexin

Integral membrane endoplasmic reticulum lectin that recognizes GlcMan9GlcNAc2 glycans on early glycoprotein folding intermediates and, in collaboration with an associated thiol oxidoreductase, ERp57, aids in protein folding as a part of endoplasmic reticulum quality control.

Calreticulin

A soluble lectin in the lumen of the endoplasmic reticulum that contains a K-D-E-L endoplasmic reticulum retrieval sequence and, in a similar way to calnexin, binds to GlcMan9GlcNAc2 glycoprotein folding intermediates to facilitate protein folding and quality control.

ER-associated degradation

(ERAD). A protein quality control pathway in which misfolded lumenal or integral membrane proteins are recognized (often through trimmed glycan structures) for disposal by translocation into the cytosol for proteasomal degradation.

Nocodozole

A pharmacological agent that blocks mitosis by binding to tubulin and inhibiting microtubule polymerization. Inhibition of microtubule polymerization also causes the dispersal of well-organized Golgi stacks into smaller units distributed throughout the cytoplasm.

Brefeldin A

A fungally derived antibiotic that inhibits the guanine nucleotide exchange factor (GEF) responsible for activating ARF1 GTPase. Activation of ARF1 recruits coatomer protein complex I (COPI) to Golgi membranes to form vesicles. In the absence of Golgi vesicle formation, cis and medial cisternae fuse with the endoplasmic reticulum and the trans and trans-Golgi network components disperse into a drug-induced entity called the brefeldin compartment.

Cisternal maturation

An early model of Golgi trafficking that proposed that Golgi cisternae formed from the fusion of vesicles leaving the endoplasmic reticulum and were subsequently matured by the import of appropriate processing enzymes as the cisternae were pushed forward towards the trans face. The original cisternal maturation model had its groundings in extensive electron microscopic observations of Golgi morphology.

Vesicular transport

A model for Golgi trafficking, which proposed that cisternae are stable structures and that cargo proteins move between cisternae in transport vesicles that are targeted to specific Golgi domains.

Rapid partitioning

A model for Golgi trafficking, which proposes that cargo proteins can exit the Golgi in vesicles arising from all cisternae and that new protein arriving at the Golgi rapidly gains access to the entire apparatus. Distinct transport and processing domains within each Golgi cistern are defined by their lipid content, which varies systematically from cis-to-trans and may provide favourable environments for cisternae-specific subsets of glycan processing enzymes.

Glycosphingolipids

Glycoconjugates comprised of a ceramide lipid (Cer) carrying a glycan headgroup. The glycan is usually initiated by Glc, although GalCer is an important component of some cells. GlcCer is elongated to generate four major types of neutral cores in mammalian tissues (ganglio-, globo-, lacto- and neolacto-series), each of which can be capped and branched to produce additional structural diversity.

Type 2 transmembrane proteins

Single pass transmembrane proteins with their amino terminus oriented towards the cytosol and their carboxyl terminus facing the lumen of the secretory pathway or cell exterior.

Vacuolar protein sorting 74

(Vps74). A yeast protein identified as having a vacuolar protein sorting function. Yeast vps74 mutants are deficient in intra-Golgi transport and exhibit mis-localized glycosyltransferases. Golgi phosphoprotein 3 (GOLPH3) is the mammalian homologue of Vps74.

Coatomer protein complex I

(COPI). A protein complex that is recruited to membranes by ARF (ADP-ribosylation factor) GTPases and that mediates intra-Golgi and Golgi-to-endoplasmic reticulum retrograde transport.

Mucin-type O-linked glycosylation

A form of protein glycosylation initiated by the addition of a GalNAc residue to protein Ser or Thr side chains and extended and branched with other complex termini. It is commonly found on highly glycosylated mucin glycoproteins, but also on many non-mucin polypeptides.

Golgins

A family of Golgi tethering factors characterized by their extended coiled-coil domains. Individual family members exhibit specific sub-Golgi localizations, GTPase interactions and effector activities. The golgins form long filaments that emanate from the cytoplasmic face of Golgi cisternae, providing access to transport vesicles in the near environment. Some golgins possess multiple binding sites for RAB proteins, suggesting that they capture transport vesicles carrying specific RAB proteins.

Conserved oligomeric Golgi complex

(COG complex). A multiprotein tethering factor comprised of eight protein subunits. The complex facilitates Golgi retrograde transport and glycosyltransferase localization.

Congenital disorders of glycosylation

(CDGs). A growing group of recessive human disorders characterized by altered protein glycosylation. In type 1 CDGs, the number of N-linked glycans added to a protein is affected. In type 2 CDGs, the nature of the glycan on a glycoprotein is changed. Most CDGs arise from partial loss-of-function mutations and are diagnosed clinically by altered serum protein glycosylation.

Retrograde transport

The movement of vesicles containing Golgi-resident proteins (glycosyltransferases and other processing enzymes) from late to early cisternae. Retrograde transport provides a mechanism for retrieving enzymes that are displaced forward by anterograde flow or cisternal maturation.

Anterograde flow

The bulk movement of cisternal contents and cargo proteins from early to late Golgi compartments.

EGF domains

Protein motifs comprised of 30–40 amino acids, including six Cys residues forming three characteristic disulphide bonds, and a mainly β-sheet structure, found in all ERBB-binding growth factors and many other cell surface and extracellular matrix proteins.

Thrombospondin type 1 repeats

(TSRs). Protein domains of 50 amino acids. They are rich in Cys residues and are comprised of three antiparallel β-strands along with regions without a secondary structure. TSRs are found in matrix and transmembrane proteins with functions in matrix organization, cell–cell interactions and cell guidance.

Dystroglycanopathies

A clinically heterogeneous collection of muscular dystrophies that are associated with aberrant glycosylation of α-dystroglycan, which is a component of the multiprotein dystrophin glycoprotein complex that bridges the extracellular matrix, plasma membrane and cytoskeleton.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Moremen, K., Tiemeyer, M. & Nairn, A. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol 13, 448–462 (2012). https://doi.org/10.1038/nrm3383

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing