Chemoenzymatic Synthesis of N-glycan Positional Isomers and Evidence for Branch Selective Binding by Monoclonal Antibodies and Human C-type Lectin Receptors

Echeverría, Begoña; Serna, Sonia; Achilli, Silvia; Vivès, Corinne; Pham, Julie; Thépaut, Michel; Hokke, Cornelis H.; Fieschi, Franck; Reichardt, Niels‐Christian

doi:10.1021/acschembio.8b00431

Cited by 40 publications

(55 citation statements)

References 60 publications

(120 reference statements)

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“…The fact that residues from the HsFUT8 SH3 domain recognize sugar moieties implies the broad versatility of these domains in recognition of different molecules; and (d) the most intimately recognition for the α1,3 arm GlcNAc explains why FUT8 requires the presence of a terminal GlcNAc moiety on the α1,3 arm of the N-glycan for optimal fucosylation. This ligand-binding model also explains our own data using HsFUT8 on a microarray of synthetic N-glycans and prior reports 10,13,14 . However, our structure does not offer clues on how FUT8 fucosylates less optimally high mannose N-glycans linked to glycoproteins and peptides that lack a terminal GlcNAc on the α1,3-branch and which will require further structural studies.…”

Section: Discussionsupporting

confidence: 82%

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Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

et al. 2020

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Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an S N 2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.

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Section: Discussionsupporting

confidence: 82%

“…1). Then, we evaluated the HsFUT8 acceptor substrate specificity on a microarray of synthetic N-glycans by expanding an earlier array version used by us in the study of C. elegans FUT8 (CeFUT8) 13,14 (Fig. 1, Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

et al. 2020

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“…To begin to understand these processes from an atomistic level of detail, as a first step Although the existence of 'folded-over' (and variation there-of) and of 'outstretched' conformations of the a(1-6) arm have been identified and discussed previously [41][42] , our systematic study highlights the unique dependence of this conformational propensity on the galactosylation of the a(1-6) arm. This behaviour can explain the recent evidence of differential recognition of positional isomers in glycan array screening 43 . As an example, the positional isomers sugar J and L have a galactose on either the a(1-3) or the a(1-6) arm, respectively, which confers a different conformational propensity of the a(1-6) arm.…”

Section: Discussionmentioning

confidence: 53%

“…This effect is determined by more effective hydrogen bonding and stacking interactions of the chitobiose with the 'longer' galactosylated a(1-6) arm and it is independent of the sequence of the a(1-3) arm, of core-fucosylation and of sialylation of the a(1-6) arm. These results can explain the differential recognition of positional isomers 43 and with the preference of sialyltransferases for the a(1-3) arm in both, isolated and Fc-linked N-glycans.…”

Section: Discussionmentioning

confidence: 85%

Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: A molecular dynamics study

Harbison

Brosnan

Fenlon

et al. 2018

Preprint

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Fc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function. Indeed, while core-fucosylation of IgG Fcglycans greatly affects the antibody-dependent cell-mediated cytotoxicity (ADCC) function, with obvious repercussions in the design of therapeutic antibodies, sialylation can reverse the antibody inflammatory response, and galactosylation levels have been linked to aging, to the onset of inflammation, and to the predisposition to rheumatoid arthritis. Within the framework of a structure-to-function relationship, we have studied the role of the N-glycan sequence on its intrinsic conformational propensity. Here we report the results of a systematic study, based on extensive molecular dynamics (MD) simulations in excess of 62 µs of cumulative simulation time, on the effect of sequence on the structure and dynamics of increasingly larger, complex biantennary N-glycoforms, i.e. from chitobiose to the larger N-glycan species commonly found in the Fc region of human IgGs. Our results show that while core fucosylation and sialylation do not affect the intrinsic dynamics of the isolated (unbound) N-glycans, galactosylation of the a(1-6) arm shifts dramatically its conformational equilibrium from an outstretched to a folded conformation. These findings are in agreement with and can help rationalize recent experimental evidence showing a differential recognition of positional isomers in glycan array data and also the preference of sialyltransferase for the more reachable, outstretched a(1-3) arm in both isolated and Fc-bound N-glycans.

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“…Dissimilarly to proteins or nucleic acids, which are linear, the glycosidic linkage in oligosaccharides have multiple attach points on the sugar ring, thus allowing both linear and branched structures (called antennae) [7]. The majority of bi-, tri-, and tetra-antennary glycans found in nature have diverse sugar residues linked to the terminal N-acetylglucosamine (GlcNAc) giving rise to distinct glycan determinants [79].…”

Section: Food Glycans and Antigensmentioning

confidence: 99%

Blood Type Diets (BTD) and Aging: An Overview

Menapace¹

2019

J Aging Sci

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It has recently been proposed that glycans, being the third alphabet of life, interact intricately with endogenous biomolecules to modulate tolerance, immune and inflammatory responses. Specifically, food glycans could impact health and be a source of inflammation and age-related diseases. These special carbohydrates are present as glycoconjugates (glycoproteins or glycolipids) in and on the surface of all the cells (glycocalyx) of all organisms or are found in free form in biological fluids. Recent advances in glycobiology and glycochemistry have shown how glycans bind with naturally present human proteins (lectins), through protein-carbohydrate interactions (or PCI), but also how oligosaccharides can interact with other glycans, present throughout the human body (through carbohydrate-carbohydrate interactions, or CCI). Oligosaccharides present in food sources, which go beyond the definition of normal fibers, once ingested are then either absorbed in the bloodstream, where they are recognized by the immune system, or interact with the surface of GI epithelial cells, thus generating appropriate biochemical cascades that induce a tolerance or immune/inflammatory response. Because the ABO epitopes have been encountered on all human cells, not just erythrocytes and based on the different biotypology (A, AB, B, and O) impose morphic changes in the distribution of the glycans on the glycocalyx (lipid rafts and clustered saccharide patches), their CCI with food and microbe glycans will be different, thus, eliciting contrasting responses. This can explain the epidemiological data for blood type diets (BTD). Through continuous consumption of the wrong types of glycans, processes of chronic inflammation could be initiated and progress to accelerated aging. Four basic modes of action have been identified showing how glycans can trigger inflamm-aging. Since glycobiology is a young science, further studies with newer technologies are warranted for advancement in this field.

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Chemoenzymatic Synthesis of N-glycan Positional Isomers and Evidence for Branch Selective Binding by Monoclonal Antibodies and Human C-type Lectin Receptors

Cited by 40 publications

References 60 publications

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: A molecular dynamics study

Blood Type Diets (BTD) and Aging: An Overview

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