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Glycobiology Advance Access published online on December 17, 2002
Glycobiology, doi:10.1093/glycob/cwg026
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Submitted on May 2, 2002
Revised on July 22, 2002
Accepted on July 26, 2002

© 2002 Oxford University Press

ORIGINAL ARTICLES

The underglycosylation of plasma {alpha}1-antitrypsin in congenital disorders of glycosylation type I (CDG-I) is not random

Kevin Mills 1, Philippa B. Mills 1, Peter T. Clayton 1, Nasi Mian 1, Andrew W. Johnson 1, Bryan G. Winchester 1*

1 Biochemistry Endocrinology and Metabolism Unit, Institute of Child Health at Great Ormond Street Hospital, University College London, 30 Guilford Street, London, WC1N 1EH, UK

* To whom correspondence should be addressed. E-mail: B.Winchester{at}ich.ucl.ac.uk.

Abstract

Conditions under which the glycosylation capacity of cells is limited provide an opportunity for studying the efficiency of site-specific glycosylation and the role of glycosylation in the maturation of glycoproteins. The congenital disorders of glycosylation type 1 (CDG-I), which are characterised by underglycosylation of glycoproteins, due to defects in the assembly or transfer of the common dolichol-pyrophosphate-linked oligosaccharide precursor of asparagine-linked glycans, provide such a system. Human plasma {alpha}1-antitrypsin is normally fully glycosylated at three asparagine residues, 46, 83 and 247 but unglycosylated, mono-, di-, and fully glycosylated forms of {alpha}1-antitrypsin were detected by 2D-PAGE in the plasma from patients with CDG-I. The state of glycosylation of the three asparagine residues was analysed in all the underglycosylated forms of {alpha}1-antitrypsin by peptide mass fingerprinting using matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI TOF MS). It was found that asparagine 46 was always glycosylated and that asparagine 83 was never glycosylated in the underglycosylated glycoforms of {alpha}1-antitrypsin. This showed that the asparagine residues are preferentially glycosylated in the order 46>247>83 in the mature underglycosylated forms of {alpha}1-antitrypsin found in plasma. It is concluded that the non-occupancy of glycosylation sites is not random under conditions of decreased glycosylation capacity and that the efficiency of glycosylation site occupancy depends on structural features at each site. The implications of this observation for the intracellular transport and sorting of glycoproteins are discussed.


Keywords: {alpha}1-antitrypsin, 2D-PAGE, MALDI TOF MS, CDG.
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