Critical Reviews in Oral Biology & Medicine, Vol 9, 415-448, Copyright © 1998 by International & American Associations for Dental Research

ARTICLES

Protein N-glycosylation: molecular genetics and functional significance

M. A. Kukuruzinska and K. Lennon
Department of Molecular and Cell Biology, School of Dental Medicine, Boston University Medical Center, Massachusetts 02118, USA.

Protein N-glycosylation is a metabolic process that has been highly conserved in evolution. In all eukaryotes, N-glycosylation is obligatory for viability. It functions by modifying appropriate asparagine residues of proteins with oligosaccharide structures, thus influencing their properties and bioactivities. N-glycoprotein biosynthesis involves a multitude of enzymes, glycosyltransferases, and glycosidases, encoded by distinct genes. The majority of these enzymes are transmembrane proteins that function in the endoplasmic reticulum and Golgi apparatus in an ordered and well-orchestrated manner. The complexity of N-glycosylation is augmented by the fact that different asparagine residues within the same polypeptide may be modified with different oligosaccharide structures, and various proteins are distinguished from one another by the characteristics of their carbohydrate moieties. Furthermore, biological consequences of derivatization of proteins with N-glycans range from subtle to significant. In the past, all these features of N-glycosylation have posed a formidable challenge to an elucidation of the physiological role for this modification. Recent advances in molecular genetics, combined with the availability of diverse in vivo experimental systems ranging from yeast to transgenic mice, have expedited the identification, isolation, and characterization of N-glycosylation genes. As a result, rather unexpected information regarding relationships between N-glycosylation and other cellular functions--including secretion, cytoskeletal organization, proliferation, and apoptosis--has emerged. Concurrently, increased understanding of molecular details of N-glycosylation has facilitated the alignment between N-glycosylation deficiencies and human diseases, and has highlighted the possibility of using N-glycan expression on cells as potential determinants of disease and its progression. Recent studies suggest correlations between N-glycosylation capacities of cells and drug sensitivities, as well as susceptibility to infection. Therefore, knowledge of the regulatory features of N-glycosylation may prove useful in the design of novel therapeutics. While facing the demanding task of defining properties, functions, and regulation of the numerous, as yet uncharacterized, N-glycosylation genes, glycobiologists of the 21st century offer exciting possibilities for new approaches to disease diagnosis, prevention, and cure.

This article has been cited by other articles:

				E. Kainz, A. Gallmetzer, C. Hatzl, J. H. Nett, H. Li, T. Schinko, R. Pachlinger, H. Berger, Y. Reyes-Dominguez, A. Bernreiter, et al. N-Glycan Modification in Aspergillus Species Appl. Envir. Microbiol., February 15, 2008; 74(4): 1076 - 1086. [Abstract] [Full Text] [PDF]

				A. Liwosz, T. Lei, and M. A. Kukuruzinska N-Glycosylation Affects the Molecular Organization and Stability of E-cadherin Junctions J. Biol. Chem., August 11, 2006; 281(32): 23138 - 23149. [Abstract] [Full Text] [PDF]

				J. J. Smith, D. W. Conrad, M. J. Cuneo, and H. W. Hellinga Orthogonal site-specific protein modification by engineering reversible thiol protection mechanisms Protein Sci., January 1, 2005; 14(1): 64 - 73. [Abstract] [Full Text] [PDF]

				P. Bobrowicz, R. C. Davidson, H. Li, T. I. Potgieter, J. H. Nett, S. R. Hamilton, T. A. Stadheim, R. G. Miele, B. Bobrowicz, T. Mitchell, et al. Engineering of an artificial glycosylation pathway blocked in core oligosaccharide assembly in the yeast Pichia pastoris: production of complex humanized glycoproteins with terminal galactose Glycobiology, September 1, 2004; 14(9): 757 - 766. [Abstract] [Full Text] [PDF]

				R. C. Davidson, J. H. Nett, E. Renfer, H. Li, T. A. Stadheim, B. J. Miller, R. G. Miele, S. R. Hamilton, B.-K. Choi, T. I. Mitchell, et al. Functional analysis of the ALG3 gene encoding the Dol-P-Man: Man5GlcNAc2-PP-Dol mannosyltransferase enzyme of P. pastoris Glycobiology, May 1, 2004; 14(5): 399 - 407. [Abstract] [Full Text] [PDF]

				R. Misaki, Y. Kimura, N. Q. Palacpac, S. Yoshida, K. Fujiyama, and T. Seki Plant cultured cells expressing human {beta}1,4-galactosyltransferase secrete glycoproteins with galactose-extended N-linked glycans Glycobiology, March 1, 2003; 13(3): 199 - 205. [Abstract] [Full Text] [PDF]

				T. de Vries, J. Storm, F. Rotteveel, G. Verdonk, M. van Duin, D. H. van den Eijnden, D. H. Joziasse, and H. Bunschoten Production of soluble human {alpha}3-fucosyltransferase (FucT VII) by membrane targeting and in vivo proteolysis Glycobiology, September 1, 2001; 11(9): 711 - 717. [Abstract] [Full Text] [PDF]

				A. Lux, C. J. Gallione, and D. A. Marchuk Expression analysis of endoglin missense and truncation mutations: insights into protein structure and disease mechanisms Hum. Mol. Genet., March 22, 2000; 9(5): 745 - 755. [Abstract] [Full Text] [PDF]

				N. Q. Palacpac, S. Yoshida, H. Sakai, Y. Kimura, K. Fujiyama, T. Yoshida, and T. Seki Stable expression of human beta 1,4-galactosyltransferase in plant cells modifies N-linked glycosylation patterns PNAS, April 13, 1999; 96(8): 4692 - 4697. [Abstract] [Full Text] [PDF]