DOC PREVIEW
UGA BCMB 8020 - Rudd2004

This preview shows page 1-2 out of 7 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 7 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

Sugar-mediated ligand-receptor interactions in the immune systemGlycan analysisGlc1Man9-7GlcNAc2 oligosaccharides bind subsites on calnexinStructural role of sugars in the T cell synapseClusters of specific IgG sugars bind MBLSecretory IgA glycans bind bacteriaThe immunologically ‘silent’ heavily glycosylated face of HIV gp120 binds IgG 2G12ConclusionReferencesSugar-mediated ligand–receptorinteractions in the immune systemPauline M. Rudd, Mark R. Wormald and Raymond A. DwekOxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UKMost molecules involved in the recognition and elimin-ation of pathogens by the immune system are glyco-proteins. Oligosaccharides attached to glycoproteinsinitiate biological functions through mechanisms thatinvolve multiple interactions of the monosaccharideresidues with receptors. For example, calreticulin, aquality-control lectin-like chaperone, interacts withglucosylated mannose glycans presented by emptymajor histocompatibility complex (MHC) class I mol-ecules, retaining them in the endoplasmic reticulum (ER)until antigenic peptide is loaded. Clusters of specific IgGglycoforms, present in increased amounts in rheuma-toid arthritis, bind mannose-binding lectin (MBL), pro-viding a potential route to inflammation throughactivation of the complement pathway. Secretory IgAglycans bind gut bacteria, and an unusual cluster ofmannose residues on gp120, the surface coat protein ofthe HIV virus, is recognized by the novel ‘domain-swapped’ IgG 2G12 serum antibody.Glycosylation is essential for life. Almost all organismsincluding fungi, yeast, plants, insects, fish, birds andmammals glycosylate most of their secreted and cell-surface proteins. In addition, viruses, which have noglycosylation machinery of their own, attach sugars totheir envelope proteins by exploiting the biosyntheticpathways of their hosts. The essential role of glycosylationin viability has been demonstrated in knockout mice. TheMgat1 gene encodes N-acetylglucosamine transferase I,an enzyme required in the processing of complex typesugars (Box 1). When Mgat1 was deleted in mice, theoffspring died after 9 days in embryo as a result of defectsin vascularization and neural tube closure [1]. Similarly,deletion of the Mgat2 gene, encoding N-acetylglucosaminetransferase II, which is also necessary for processingcomplex type sugars, caused frequent postnatal lethalityand 99% of the mice died within the first week of birth [2].In the immune system, oligosaccharides attached toboth host and pathogenic proteins have many roles thatare both structural and functional (Box 2). In this reviewwe discuss some of these roles, focusing in particular onrecognition events in which oligosaccharides generallyinitiate biological functions through mechanisms thatinvolve multiple interactions of the monosaccharideresidues with receptors. This requirement for multi-valency is a vital means of ensuring that physiologicalconsequences generated by the activation of signallingpathways are not triggered inadvertently by single weakinteractions, but only in response to a strong stimulus.Although individual monosaccharides have low affinity forprotein receptors – usually in the millimolar to micro-molar range – two mechanisms enable oligosaccharideligands to interact with their receptors with high affinityor avidity.The first mechanism requires the presence of subsitesin the receptor, each of which can accommodate amonosaccharide residue with very different affinities. Anexample of such a receptor is the quality-control lectin-likechaperone calnexin, which can interact with a tetrasac-charide epitope presented by an unfolded glycoprotein,thereby retaining the glycoprotein in the ER (see below).The second mechanism depends on the presentation ofmultiple oligosaccharides in such a way that the sugarscan interact with several carbohydrate recognition siteson the receptor. An example of this mechanism is thefunctional binding of the carbohydrate recognitiondomains of MBL to specific aggregated IgG glycoformsthat present arrays of terminal N-acetylglucosamineresidues (see below). Insights into some of the ligand–receptor interactions that involve glycoproteins in theimmune system have come from combining glycananalysis, protein structural data and biochemical datawith molecular modelling.In general, oligosaccharides confer stability on glyco-proteins and protect them from proteases and nonspecificprotein–protein interactions, but, as we review here, someoligosaccharides form specific recognition epitopes thathave functional consequences on receptor binding.Roughly 80% of secreted and cell-surface proteins areglycosylated. In the ER, N-linked sugars are usuallyattached co-translationally to partially folded proteinsthrough the side chains of asparagine residues containedin the consensus sequence Asn-Xaa-Ser/Thr (where Xaa isany amino acid except proline). The fully folded proteinsare transported to the Golgi, where N-linked glycansare further processed to complex type oligosaccharidesand O-glycans can be added to accessible side chains ofserine or threonine residues [3,4].Notably, molecular modelling of both proteins andtheir attached oligosaccharides provides graphic illus-trations of the finding that the sugars frequently occupy alarger three-dimensional space than do the proteindomains to which they are attached. Although glyco-proteins usually consist of an ensemble of glycosylatedCorresponding author: Pauline M. Rudd ([email protected]).Available online 14 August 2004www.sciencedirect.com 0167-7799/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2004.07.012Review TRENDS in Biotechnology Vol.22 No.10 October 2004variants (‘glycoforms’), specific sugar epitopes required forrecognition might be a feature of many glycoforms, andthus a complete glycan analysis is required if suchstructures are to be identified.Glycan analysisState-of-the-art glycan analysis of scarce biological glyco-proteins is based on a combination of high-performanceliquid chromatography (HPLC) analysis and mass spectro-metry. Exogl ycosidase array digestions provide mono-saccharide and linkage information and, if sufficientmaterial is available, mass spectrometry fragmentationdata can also provide composition and linkage information.The analytical strategy used in the Oxford GlycobiologyInstitute is shown in Figure 1. Glycans are


View Full Document

UGA BCMB 8020 - Rudd2004

Download Rudd2004
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Rudd2004 and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Rudd2004 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?