‘Naked’ and Hydrated Conformers of the Conserved Core Pentasaccharide of N-linked Glycoproteins and Its Building BlocksClick to copy article linkArticle link copied!
- Conor S. Barry
- Emilio J. Cocinero
- Pierre Çarçabal
- David P. Gamblin
- E. Cristina Stanca-Kaposta
- Sarah M. Remmert
- María C. Fernández-Alonso
- Svemir Rudić
- John P. Simons
- Benjamin G. Davis
Abstract
N-glycosylation of eukaryotic proteins is widespread and vital to survival. The pentasaccharide unit −Man3GlcNAc2– lies at the protein-junction core of all oligosaccharides attached to asparagine side chains during this process. Although its absolute conservation implies an indispensable role, associated perhaps with its structure, its unbiased conformation and the potential modulating role of solvation are unknown; both have now been explored through a combination of synthesis, laser spectroscopy, and computation. The proximal −GlcNAc-GlcNAc– unit acts as a rigid rod, while the central, and unusual, −Man-β-1,4-GlcNAc– linkage is more flexible and is modulated by the distal Man-α-1,3– and Man-α-1,6– branching units. Solvation stiffens the ‘rod’ but leaves the distal residues flexible, through a β-Man pivot, ensuring anchored projection from the protein shell while allowing flexible interaction of the distal portion of N-glycosylation with bulk water and biomolecular assemblies.
Introduction
Figure 1
Figure 1. The pivotal role of the core pentasaccharide in N-glycoproteins. (a) The conserved core pentasaccharide motif, (Man3GlcNAc2 shown in gray box), is attached to asparagine residues of glycoproteins (N, S, and T denote asparagine, serine, and threonine, X denotes any amino acid but not proline). Proteins are cotranslationally modified with a tetradecasaccharide which is tailored by glycosyl-hydrolase and transferase enzymes to create diverse glycans with varying antennae but all based upon the conserved core pentasaccharide (gray box). (b) The structures and symbol representations of the core pentasaccharide 4 and the building blocks 1–3 from key regions of 4 used in this study. The naming convention A–E is used in this manuscript to identify the individual glycosyl residues. The site of the benign chromophore used in this study mimics the location of the protein scaffold or truncated glycan (shown by a red star).
Methods
Experimental Section
Computational
Results and Discussion
Design of the Glycan Targets
Figure 2
Figure 2. Schematic of synthetic strategy toward the core pentasaccharide and its building blocks. Synthesis of the core pentasaccharide 4 and its building blocks 1–3 shown using symbol representations. The chromophore used in this study, phenyl, is shown by a red star. For full synthetic details and structures see Figure S1 for the steps describing the conversion of 5 to 1–3 and intermediate 9; Figure S2 for conversion of 18, 19, and 9 onward to 4. All glycosylations were accomplished with >98% stereoselectivity for α- (αG) or β- (βG) glycosidic linkages through the use of participatory C-2 ester substituents (Ac or Lev).
Synthesis of the Proximal (GlcNAc21), Central (Man-GlcNAc 2), and Extended Stem (Man-GlcNAc-GlcNAc 3) Building Blocks
Synthesis of the Chromophore-Tagged Core Pentasaccharide 4
The Gas-Phase IRID Spectra and Structures of Building Blocks 1–3
Figure 3
Figure 3. The IR ion depletion (IRID) spectra, computed vibrational spectra and structures of 1, 2, and 3. σ1,2, ... and σNH indicate the OH and NH vibrational mode assignments; relative energies (at 0 K) and free energies (at 298 K), kJ mol–1, are shown in brackets. Structural assignments are based first on the correspondence between the experimental (IRID) and computed vibrational spectra and second on their relative energies, favoring the most stable conformer(s). (a) The computed vibrational spectrum of the trans conformation of 1 predicted as the global minimum, corresponded best with the experimental IRID spectrum associated with the major conformer (1-trans) while the lowest-lying cis conformation corresponded to the IRID signature of the minor conformer (1-cis). (b) The IRID and computed vibrational spectra associated with the three lowest-energy conformations of ManC-β1,4-GlcNAcB2; the two lowest (which differ only in the orientation of the hydroxymethyl group on the mannopyranoside ring) both display 2-cis conformations. The commonly observed B-ring acetamido → OH-3 interaction in the two units 1 and 2 lends further support to the ‘building block’ approach adopted here. (c) The calculated spectrum associated with the lowest energy, cis–cis conformer of 3 is in good qualitative agreement with the IRID spectrum of the trisaccharide 3, ManC-β1,4-GlcNAcB-β1,4-GlcNAcA.
Hydrated and ‘Blocked’ Conformations of 1–3
Figure 4
Figure 4. Hydrated and ‘blocked’ structures of the core pentasaccharide building blocks. The computed lowest-energy structures of (a,b), the monohydrates 1·H2O and 2·H2O and (c,d) the “blocked” subunits 2-B and 2-B·H2O, in which the 6-OHC group is modified to the methyl ether, and (e) the blocked subunit 3-B. Note the effect of blocking; in 2-B·H2O it removes the water bridge present in 2·H2O (and 1·H2O), and in 2-B and 3-B it switches the conformation about the ManC-β1,4C-GlcNAcB linkage from cis to trans. Gray dotted circles indicate ‘blocked’ sites, explored here through the use of a methyl ether capping group. Red dotted circles indicate a water binding site.
Gas-Phase Spectra and Structures of the Core Pentasaccharide 4
Figure 5
Figure 5. Spectra of the core pentasaccharide. (a) Resonant two-photon ionization (R2PI) spectra of the chitobiose stem, 1, the trisaccharide linker, 3, and the complete core pentasaccharide, 4. (b) The IRID spectrum of 4.
Figure 6
Figure 6. The spectra and structures of the core pentasaccharide 4. (a) The lowest-energy structures of the core pentasaccharide calculated on the OPLS2005 and GLYCAM06/AMBER potential energy surfaces: (i) the isolated molecule; (ii) the triply hydrated complex (the water molecules were initially located at binding sites based upon the preferences of singly hydrated 1, 2, and the trimannosyl ManE(ManD)ManC– head unit (15)); and (iii) in bulk water, (hydrogen bonds shown in red). (iv) An overlay of the “open” conformer of the trimannosyl ManE(ManD)ManC– head unit and the core pentasaccharide in (v); (v) the preferred aqueous structure of the high mannose glycan, Man9GlcNAc2, determined through NMR measurements and molecular dynamics simulations. (12, 13) Red dots represent transiently bound water molecules. (b) Distributions of the longest intramolecular distances (for conformers with energies <30 kJ mol–1) in the core pentasaccharide, predicted by molecular mechanics (OPLS2005) simulations: isolated, unsolvated (red), explicitly hydrated (green), and in bulk water (black).
Discussion and Conclusions
Figure 7
Figure 7. An extrapolated structural model for the N-glycan core in an aqueous environment. In the absence of water (a), the pentasaccharide would adopt a compact conformation, but the interactions between the building blocks of the core pentasaccharide and water (b) lead, in solution (c), to a rigid chitobiose stem that is anchored at one end to the peptide (10, 11, 59) and at the other, through a flexible ‘pivot’, to a β-mannosyl structure that projects the information-rich distal head of the glycan for interaction with other partners. The red dots indicate favored water-bridging sites identified here or in previous investigations. (15)
Supporting Information
Synthetic methods; NMR data; spectroscopic and computational methods; computed relative energies, vibrational frequencies, and structural data. This material is available free of charge via the Internet at http://pubs.acs.org.
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgment
We are grateful to the following for their support: the Leverhulme Trust for the award of an Emeritus Fellowship (J.P.S.); the Royal Society and the Wolfson Foundation for a Research Merit Award (B.G.D.); the EPSRC (B.G.D., J.P.S.); the Spanish Ministry (MICINN) for a project CTQ2011-22923 and “Ramón y Cajal” Contract (E.J.C.); the STFC for the provision of equipment from the Laser Loan Pool; the Oxford Supercomputing Centre and SGIker at UPV-EHU. We are especially grateful for the advice and assistance provided Professor Jesus Jiménez-Barbero and Professor David Clary and thank Dr. Mark Wormald for helpful discussions. Experiments performed in Orsay were supported by Triangle de la Physique, contract 2010-079T.
References
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Abstract
Figure 1
Figure 1. The pivotal role of the core pentasaccharide in N-glycoproteins. (a) The conserved core pentasaccharide motif, (Man3GlcNAc2 shown in gray box), is attached to asparagine residues of glycoproteins (N, S, and T denote asparagine, serine, and threonine, X denotes any amino acid but not proline). Proteins are cotranslationally modified with a tetradecasaccharide which is tailored by glycosyl-hydrolase and transferase enzymes to create diverse glycans with varying antennae but all based upon the conserved core pentasaccharide (gray box). (b) The structures and symbol representations of the core pentasaccharide 4 and the building blocks 1–3 from key regions of 4 used in this study. The naming convention A–E is used in this manuscript to identify the individual glycosyl residues. The site of the benign chromophore used in this study mimics the location of the protein scaffold or truncated glycan (shown by a red star).
Figure 2
Figure 2. Schematic of synthetic strategy toward the core pentasaccharide and its building blocks. Synthesis of the core pentasaccharide 4 and its building blocks 1–3 shown using symbol representations. The chromophore used in this study, phenyl, is shown by a red star. For full synthetic details and structures see Figure S1 for the steps describing the conversion of 5 to 1–3 and intermediate 9; Figure S2 for conversion of 18, 19, and 9 onward to 4. All glycosylations were accomplished with >98% stereoselectivity for α- (αG) or β- (βG) glycosidic linkages through the use of participatory C-2 ester substituents (Ac or Lev).
Figure 3
Figure 3. The IR ion depletion (IRID) spectra, computed vibrational spectra and structures of 1, 2, and 3. σ1,2, ... and σNH indicate the OH and NH vibrational mode assignments; relative energies (at 0 K) and free energies (at 298 K), kJ mol–1, are shown in brackets. Structural assignments are based first on the correspondence between the experimental (IRID) and computed vibrational spectra and second on their relative energies, favoring the most stable conformer(s). (a) The computed vibrational spectrum of the trans conformation of 1 predicted as the global minimum, corresponded best with the experimental IRID spectrum associated with the major conformer (1-trans) while the lowest-lying cis conformation corresponded to the IRID signature of the minor conformer (1-cis). (b) The IRID and computed vibrational spectra associated with the three lowest-energy conformations of ManC-β1,4-GlcNAcB2; the two lowest (which differ only in the orientation of the hydroxymethyl group on the mannopyranoside ring) both display 2-cis conformations. The commonly observed B-ring acetamido → OH-3 interaction in the two units 1 and 2 lends further support to the ‘building block’ approach adopted here. (c) The calculated spectrum associated with the lowest energy, cis–cis conformer of 3 is in good qualitative agreement with the IRID spectrum of the trisaccharide 3, ManC-β1,4-GlcNAcB-β1,4-GlcNAcA.
Figure 4
Figure 4. Hydrated and ‘blocked’ structures of the core pentasaccharide building blocks. The computed lowest-energy structures of (a,b), the monohydrates 1·H2O and 2·H2O and (c,d) the “blocked” subunits 2-B and 2-B·H2O, in which the 6-OHC group is modified to the methyl ether, and (e) the blocked subunit 3-B. Note the effect of blocking; in 2-B·H2O it removes the water bridge present in 2·H2O (and 1·H2O), and in 2-B and 3-B it switches the conformation about the ManC-β1,4C-GlcNAcB linkage from cis to trans. Gray dotted circles indicate ‘blocked’ sites, explored here through the use of a methyl ether capping group. Red dotted circles indicate a water binding site.
Figure 5
Figure 5. Spectra of the core pentasaccharide. (a) Resonant two-photon ionization (R2PI) spectra of the chitobiose stem, 1, the trisaccharide linker, 3, and the complete core pentasaccharide, 4. (b) The IRID spectrum of 4.
Figure 6
Figure 6. The spectra and structures of the core pentasaccharide 4. (a) The lowest-energy structures of the core pentasaccharide calculated on the OPLS2005 and GLYCAM06/AMBER potential energy surfaces: (i) the isolated molecule; (ii) the triply hydrated complex (the water molecules were initially located at binding sites based upon the preferences of singly hydrated 1, 2, and the trimannosyl ManE(ManD)ManC– head unit (15)); and (iii) in bulk water, (hydrogen bonds shown in red). (iv) An overlay of the “open” conformer of the trimannosyl ManE(ManD)ManC– head unit and the core pentasaccharide in (v); (v) the preferred aqueous structure of the high mannose glycan, Man9GlcNAc2, determined through NMR measurements and molecular dynamics simulations. (12, 13) Red dots represent transiently bound water molecules. (b) Distributions of the longest intramolecular distances (for conformers with energies <30 kJ mol–1) in the core pentasaccharide, predicted by molecular mechanics (OPLS2005) simulations: isolated, unsolvated (red), explicitly hydrated (green), and in bulk water (black).
Figure 7
Figure 7. An extrapolated structural model for the N-glycan core in an aqueous environment. In the absence of water (a), the pentasaccharide would adopt a compact conformation, but the interactions between the building blocks of the core pentasaccharide and water (b) lead, in solution (c), to a rigid chitobiose stem that is anchored at one end to the peptide (10, 11, 59) and at the other, through a flexible ‘pivot’, to a β-mannosyl structure that projects the information-rich distal head of the glycan for interaction with other partners. The red dots indicate favored water-bridging sites identified here or in previous investigations. (15)
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Supporting Information
Supporting Information
Synthetic methods; NMR data; spectroscopic and computational methods; computed relative energies, vibrational frequencies, and structural data. This material is available free of charge via the Internet at http://pubs.acs.org.
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