Glycan–protein interactions determine kinetics of <i>N</i>-glycan remodeling

Mathew, Corina; Weiß, Richard; Giese, Christoph; Lin, Chi Feng; Losfeld, Marie-Estelle; Glockshuber, Rudi; Riniker, Sereina; Aebi, Markus

doi:10.1039/d1cb00019e

Cited by 19 publications

(34 citation statements)

References 69 publications

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“…The lack of certain glycans at some specific sites indicated that glycosylation and processing had been sterically hindered at these sites, as analyzed and discussed for a S3. (a) α 5 integrin and (b) β 1 integrin few endogenous (Mathew et al, 2021) and viral proteins (Allen et al, 2021;Khatri et al, 2016). This and other mechanisms (Moremen & Haltiwanger, 2019) may explain the striking site specific variations in glycan profiles that were observed here.…”

Section: Overview and Molecular Modelsupporting

confidence: 51%

“…Hence, all integrin molecules that were analyzed here must have passed through the entire biosynthetic ER‐Golgi pathway, as expected from the activity‐based purification scheme (Figure 1). The lack of certain glycans at some specific sites indicated that glycosylation and processing had been sterically hindered at these sites, as analyzed and discussed for a few endogenous (Mathew et al., 2021) and viral proteins (Allen et al., 2021; Khatri et al., 2016). This and other mechanisms (Moremen & Haltiwanger, 2019) may explain the striking site specific variations in glycan profiles that were observed here.…”

Section: Resultsmentioning

confidence: 99%

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Site‐specific N‐glycan profiles of α₅β₁ integrin from rat liver

Mirgorodskaya

Dransart

Shafaq-Zadah

et al. 2022

Biology of the Cell

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Background Information: Like most other cell surface proteins, α 5 β 1 integrin is glycosylated, which is required for its various activities in ways that mostly remain to be determined. Results: Here, we have established the first comprehensive site-specific glycan map of α 5 β 1 integrin that was purified from a natural source, that is, rat liver. This analysis revealed striking site selective variations in glycan composition. Complex bi, tri, or tetraantennary N-glycans were predominant at various proportions at most potential N-glycosylation sites. A few of these sites were nonglycosylated or contained high mannose or hybrid glycans, indicating that early N-glycan processing was hindered. Almost all complex N-glycans had fully galactosylated and sialylated antennae. Moderate levels of core fucosylation and high levels of O-acetylation of NeuAc residues were observed at certain sites. An O-linked HexNAc was found in an EGF-like domain of β 1 integrin. The extensive glycan information that results from our study was projected onto a map of α 5 β 1 integrin that was obtained by homology modeling. We have used this model for the discussion of how glycosylation might be used in the functional cycle of α 5 β 1 integrin. A striking example concerns the involvement of glycanbinding galectins in the regulation of the molecular homeostasis of glycoproteins at the cell surface through the formation of lattices or endocytic pits according to the glycolipid-lectin (GL-Lect) hypothesis. Conclusion:We expect that the glycoproteomics data of the current study will serve as a resource for the exploration of structural mechanisms by which glycans control α 5 β 1 integrin activity and endocytic trafficking. Significance: Glycosylation of α 5 β 1 integrin has been implicated in multiple aspects of integrin function and structure. Yet, detailed knowledge of its glycosylation, notably the specific sites of glycosylation, is lacking. Furthermore, the α 5 β 1 integrin preparation that was analyzed here is from a natural source, which is of importance as there is not a lot of literature in the field about the glycosylation of "native" glycoproteins.

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Section: Overview and Molecular Modelsupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Site‐specific N‐glycan profiles of α₅β₁ integrin from rat liver

Mirgorodskaya

Dransart

Shafaq-Zadah

et al. 2022

Biology of the Cell

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“…Additionally, our MD simulations revealed protein-glycan interactions between D150 and N -glycans attached to N113 and N206 by hydrogen bond formation. It was previously shown by biochemical in vitro assays and computational studies that such interactions decrease glycan accessibility, which might interfere with glycan trimming as well as with EndoH f -mediated removal of N -glycans (52). The potential presence of fucosylated N -glycans such as Man 5 GlcNAc 2 Fuc is a result of fucosyltransferase FUT8 activity, which was reported to act on Man 5 GlcNAc 2 glycans (41, 53, 54).…”

Section: Discussionmentioning

confidence: 99%

N-glycosylation modulates enzymatic activity ofTrypanosoma congolensetrans-sialidase

Rosenau

Grothaus

Yang

et al. 2021

Preprint

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Trypanosomes cause the devastating disease trypanosomiasis, in which the action of trans-sialidase (TS) enzymes harbored on their surface is a key virulence factor. TS are highly N-glycosylated, but the biological functions of the glycans remain elusive. In this study, we investigated the influence of N-glycans on the enzymatic activity and structure stability of TconTS1, a recombinant TS from the African parasite Trypanosoma congolense. MALDI-TOF MS revealed that eight asparagine sites were glycosylated with high-mannose type N-glycans. Deglycosylation of TconTS1 led to a 5-fold decrease in substrate affinity but to the same conversion rate relative to the untreated enzyme. After deglycosylation, no changes in secondary structure elements were observed in circular dichroism experiments. Molecular dynamics simulations revealed interactions between the highly flexible N-glycans and some conserved amino acids belonging to the catalytic site. These interactions led to conformational changes, possibly enhancing substrate accessibility and promoting enzyme/substrate complex stability. The here-observed modulation of catalytic activity via the N-glycan shield may be a structure-function relationship intrinsic of several members of the TS family.

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“…There is a direct relationship between the spatial accessibility of the glycosylation sites and the processing state [ 48 , 49 ]. Within the context of the S glycoprotein, MD simulations have shown that the N-glycan at position N234 is one of the least accessible, in both closed and open S conformations see Figure 2 , which explains the high abundance of large oligomannose-type glycans at this site [ 6 , 33 ].…”

Section: Role Of Glycans In Protein Folding and Stabilitymentioning

confidence: 99%