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Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids.

Artikel i vetenskaplig tidskrift
Författare Jakob Cervin
Andrew Boucher
Gyusaang Youn
Per Björklund
Ville Wallenius
Lynda Mottram
Nicole S Sampson
Ulf Yrlid
Publicerad i ACS infectious diseases
ISSN 2373-8227
Publiceringsår 2020
Publicerad vid Institutionen för biomedicin
Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi
Institutionen för kliniska vetenskaper, Avdelningen för gastrokirurgisk forskning och utbildning
Språk en
Länkar dx.doi.org/10.1021/acsinfecdis.0c00...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Immunologi inom det medicinska området, Mikrobiologi inom det medicinska området, Medicinska grundvetenskaper

Sammanfattning

A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose-fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose-fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT.

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