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A Molecular Basis for Glycosylation-Induced Conformational Switching Sarah E O’Connor and Barbara Imperiali

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A Molecular Basis for Glycosylation-Induced Conformational Switching Sarah E O’Connor and Barbara Imperiali Research Paper 427 A molecular basis for glycosylation-induced conformational switching Sarah E O’Connor and Barbara Imperiali Background: Asparagine-linked glycosylation has the capacity to greatly Address: Division of Chemistry and Chemical influence the structure and function of glycoproteins. In most cases, however, it Engineering, California Institute of Technology, Pasadena, CA 91125, USA. is unclear specifically how the carbohydrate moiety interacts with the protein to influence its conformation. Correspondence: Barbara Imperiali E-mail: [email protected] Results: A series of glycopeptides based on the critical A285 glycosylation site Key words: p-turn, glycopeptide, hemagglutinin, of the hemagglutinin glycoprotein from influenza virus was used as a model peptide conformation system to study the effects of asparagine-linked glycosylation. Derivatization of this peptide with a family of short carbohydrates reveals that subtle changes in Received: 11 June 1998 the structure of the carbohydrate have a dramatic impact on peptide Accepted: 7 July 1998 conformation. Modification of the hemagglutinin glycopeptide with a truncated Published: 29 July 1998 version of the native carbohydrate induces a p-turn structure similar to the structure found in the native protein. Replacement of the C2 and C2’ N-acetyl Chemistry & Biology August 1998, 5:427-437 groups of the carbohydrates with hydroxyl moieties results in a less well-ordered http://biomednet.com/elecref/1074552100500427 peptide conformation. 0 Current Biology Publications ISSN 1074-5521 Conclusions: It is likely that the N-acetyl groups of the carbohydrates have a critical role in promoting the more compact p-turn conformation through steric interactions with the peptide. This study has demonstrated that relatively small changes in carbohydrate composition can have dramatic ramifications on glycopeptide conformation. Introduction properties of the peptide or by participating in hydrogen- Glycoproteins play a critical role in a variety of biological bonding interactions with the polypeptide [19]. Notably, processes including the immune response, cell-cell recog- evidence for specific hydrogen bonds between peptide nition and protein folding, stability and solubility [l,Z]. and carbohydrate functionality has only been observed in Glycosylation frequently has a dramatic effect on protein non-aqueous solvents. The carbohydrate might also have a structure, impacting either overall structure or local confor- steric role, in which the bulk of the carbohydrate limits mation [3]. Because N-linked glycosylation occurs co- the conformational space accessible to the peptide [ 16,201. translationally, as the protein is being biosynthesized, Definitive evidence to support any of these proposals in glycosylation-induced conformational changes could affect aqueous media has not yet been presented, however. protein folding. Indeed, numerous examples exist in which glycoproteins fail either to fold correctly or to be As the importance of N-linked glycosylation for protein secreted when certain N-linked glycosylation sites are stability and function continues to emerge, it is essential removed by site-directed mutagenesis [3-l 11. Further- to gain a full understanding of how carbohydrates influ- more, a number of short glycopeptides that mimic flexible, ence peptide structure and function. Recent advances in nascent polypeptides undergo well-defined conforma- the chemical synthesis of glycopeptides are making access tional changes after glycan derivatization [12-161. to this class of compounds easier [Zl-251. Thus, the opportunity now arises to answer specific questions con- In a few cases, the carbohydrate moiety has been shown to cerning the molecular basis of glycosylation-induced con- stabilize the structure of the fully folded protein by formational modulation. making specific, stabilizing contacts with the protein [17,18]. In systems in which these types of interactions do In our ongoing efforts to unravel the relationship between not prevail, however, understanding the mechanisms by the saccharide moiety and its effect on peptidyl structure, which carbohydrates can influence protein structure is dif- we synthesized a family of short glycopeptides in which ficult. In the absence of observable, specific carbohy- key molecular elements of the sugar, specifically the drate-protein contacts, it has been proposed that N-acetyl groups, were modulated (Figure la). The short oligosaccharides might influence the local structure of the peptide sequence AcNH-Orn-Ile-Thr-Pro-Asn-Gly- glycosylation site [1,2] either by altering the solvation Thr-Trp-Ala-CONH,, based on the essential glycosylation 428 Chemistry & Biology 1998, Vol 5 No 8 Figure 1 Chemical structures of all glycopeptides a) examined in this study. In each figure, HiQ;~;~o N-acetylglucosamine is red, and glucose NHAc is blue. v v O HNY Distal Proximal o-GlcNAc-[~(l-4)1-P-D-GlcNAc D-G~c-[~(I-~)I-~-D-GIc (Chitobiose) (Cellobiose) Glycopeptide 1 Glycopeptide 2 BM ,‘;wcz,j H”;~:.j NHAc D-Glc-[ /3(1 -4)1-p-D-GlcNAc D-GlcNAc D-GIcNAc-[~(I-~)~-~-D-GIc Glycopeptide 3 Glycopeptide 4 Glycopeptide 5 b) Chemistry & Biolog! site at residue A285 of the hemagglutinin protein of B strands [28]. For these reasons, this model peptide was influenza virus, was synthesized and derivatized with five chosen for further conformational analysis. different carbohydrates (Figure lb). The various conforma- tions of the glycopeptides were then assessed using two- Derivatizarion with a variety of saccharides (Figure 1) dimensional nuclear magnetic resonance (NMR) methods. revealed that chitobiose plays a unique role in modulat- ing peptide conformation; no other saccharide appears to Previously, two-dimensional NMR studies of glyco- definitively induce the native B-turn structure. Because peptide 1 provided evidence that glycosylation with chito- no discreet peptide-carbohydrate interactions were dis- biose, a disaccharide representing the first two B(l-4) covered, it is likely that the conformational behavior of linked N-acetylglucosamine residues of the native the saccharides is a key factor that influences peptide tetradecasaccharide, induced the formation of a compact conformation. The average structure of each glycopep- B-turn remarkably similar to the structure found in the tide in aqueous media was determined by examining fully folded glycoprotein [13,26]. Despite the dramatic nuclear Overhauser effect (NOE) data and 3JHNa values. change in peptide conformation that was observed upon To complement these structural studies, the conforma- protein glycosylation, no obvious specific interactions tional stability of the glycopeptides was assessed using between the peptide and the chitobiose moiety were 13C T, relaxation values. The results indicate that the observed in the NMR analysis. Because -30% of all glyco- addition of any carbohydrate to the asparagine sidechain sylation sites occur at sites that fold ultimately to B-turns, perturbs the aspartate/asparagine (Asx)-turn structure of this model peptide provides a relatively ‘general’ context the nonglycosylated peptide [13], but the bias towards for studying the conformational implications of N-linked B-turn structure is greatest when the truncated native glycosylation [27]. Moreover, B-turn formation is believed carbohydrate (chitobiose) is in place. Additionally, these to be critical for the protein-folding process, as folding can studies have implicated the N-acetyl group of the sugar be promoted by the long range contacts between two proximal to the peptide as a critical component required Research Paper Glycosylation-induced conformational switching O’Connor and Imperiali 429 Figure 2 Typical synthesis of an N-linked glycopeptide. The 2-hydroxy-4-methoxy group on the glycine r amide nitrogen is utilized to prevent succinimide formation (see the Materials and methods section). (a) Pd(PPh,),, (b) CHCIsIAcOHIN-methyl morpholine (37/2/l, v/v), 18 h. (b) BOP, DIPEA, glycosylamine, DMF, 8h. (c) TFA-PhOH-Ethanedithiol- OCHB OCHB triisopropylsilane (92/3/3/2 v/w/v/v). R=Glc/VAc OCH, Chemistry & Biology for the induction of p-turn formation, probably as a result (for derivatization of glycopeptide 5) were synthesized as of steric interactions with the peptide backbone. Surpris- illustrated in Figures 3 and 4. ingly, the addition of an N-acetyl group to the distal sugar also appears to play a key role in rigidifying both Glycopeptide structure the saccharide and the peptide. It should be noted that these short peptides are expected to be somewhat flexible, and that NMR-derived struc- Results and discussion tures represent a conformational average. Previous fluo- Glycopeptide synthesis rescence resonance energy transfer studies [26], along Glycopeptide synthesis was effected using the strategy with several long-range NOES (most notably, between developed by Cohen-Anisfied and Lansbury [29] and the Ile2 and Trp8 sidechains in two-dimensional ROESY Albericio and coworkers [30]. Specifically, glycopeptides experiments), suggest that these glycopeptides exhibit were prepared by coupling glycosylamines to the some prevelance of secondary structure. A structural sidechain carboxylate of an aspartic acid residue to form an analysis of the chitobiose derivative glycopeptide 1 has N-glycosidic linkage. In order to ensure regioselective been described previously (Figure 5a) [13]. In addition to coupling, an allyl-protected aspartic acid was substituted the distance restraints provided by NOESY spectra (109 for
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