Identification of glycoproteins as receptors for cholera toxin in rat intestinal microvillus membranes

Morita, Akira; Tsao, Dean; Kim, Y.S.

doi:10.1016/0016-5085(78)93270-5

Cited by 9 publications

(10 citation statements)

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“…The initial event in choleragen action is the binding of the B subunit to the cell surface receptor through specific interaction with the monosialoganglioside galactosyl-N-acetylgalactosaminyl-[N-ace-tylneuraminyll-galactosylglucosylcerarnide (GMMI) (146, 340-380), although a glycoprotein(s) has also been implicated (381,382). The A subunit, by catalyzing the ADP-ribosylation of G,,, the stimulatory G protein, is responsible for adenylate cyclase activation.…”

Section: A Choleragen: Subunit Structure and Functionmentioning

confidence: 99%

Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Moss

Vaughan

1988

Advances in Enzymology - And Related Areas of Molecular Biology

140

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Section: A Choleragen: Subunit Structure and Functionmentioning

confidence: 99%

Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Moss

Vaughan

1988

Advances in Enzymology - And Related Areas of Molecular Biology

140

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“…Thus, exogenously incorporated GM1 was functionally equivalent to endogenously induced GM~ as a receptor for choleragen. Despite the substantial evidence implicating GMt as the receptor for choleragen, several investigators have suggested that the native receptor for the toxin is more complex than GM~ [20,72,76,77,87]. To clarify the situation, studies were initiated with a line of transformed mouse fibroblasts (NCTC 2071) which had been adapted to grow in chemically defined medium 2.…”

Section: Ganglioside G M 1 Is the Receptor For Cholera Toxinmentioning

confidence: 99%

Role of membrane gangliosides in the binding and action of bacterial toxins

1982

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Gangliosides are complex glycosphingolipids that contain from one to several residues of sialic acid. They are present in the plasma membrane of vertebrate cells with their oligosaccharide chains exposed to the external environment. They have been implicated as cell surface receptors and several bacterial toxins have been shown to interact with them. Cholera toxin, which mediates its effects on cells by activating adenylate cyclase, bind with high affinity and specificity to ganglioside GM1. Toxin-resistant cells which lack GM1 can be sensitized to cholera toxin by treating them with GM1. Cholera toxin specifically protects GM1 from cell surface labeling procedures and only GM1 is recovered when toxin-receptor complexes are isolated by immunoadsorption. These results clearly demonstrate that GM1 is the specific and only receptor for cholera toxin. Although cholera toxin binds to GM1 on the external side of the plasma membrane, it activates adenylate cyclase on the cytoplasmic side of the membrane by ADP-ribosylation of the regulatory component of the cyclase. GM1 in addition to functioning as a binding site for the toxin appears to facilitate its transmembrane movement. The heat-labile enterotoxin of E. coli is very similar to cholera toxin in both form and function and can also use GM1 as a cell surface receptor. The potent neurotoxin, tetanus toxin, has a high affinity for gangliosides GD1b and GT1b and binds to neurons which contain these gangliosides. It is not yet clear whether these gangliosides are the physiological receptors for tetanus toxin. By applying the techniques that established GM1 as the receptor for cholera toxin, the role of gangliosides as receptors for tetanus toxin as well as physiological effectors may be elucidated.

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“…The two variants only differ in residues 18 and 47 in the secondary CT binding site (cCT: H18, T47, ET CT: Y18, I47) 4,20 , which is why they have been in the focus of cholera blood group binding studies 21–24 . Moreover, there is increasing evidence that GM1 is not the only CT receptor and may not even be its main receptor 18,25–31 .…”

Section: Introductionmentioning

confidence: 99%

Crystal structures reveal that Lewis-x and fucose bind to secondary cholera toxin binding site – in contrast to fucosyl-GM1

Hodnik

et al. 2018

Preprint

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13Cholera is a life-threatening diarrhoeal disease caused by the human pathogen Vibrio cholerae. 14 Infection occurs after ingestion of the bacteria, which colonize the human small intestine and 15 secrete their major virulence factorthe cholera toxin (CT). Recent studies suggest that the 16 GM1 receptor may not be the only target of the CT, and that fucosylated receptors such as 17 Lewis x (Le x ) and histo-blood group antigens may also be important for cellular uptake and 18 toxicity. However, where and how Le x binds to the CT remains unclear. Here we report the high-19resolution crystal structure (1.5 Å) of the receptor-binding B-subunit of the CT bound to the Le x 20 trisaccharide, and present matching SPR data for CT holotoxins. Le x , and also L-fucose alone (at 21 500-fold molar excess), bind to the secondary binding site of the toxin, distinct from the GM1 22 binding site. In contrast, fucosyl-GM1 binds to the primary binding sites due to high-affinity 23 interactions of its GM1 core. The two binding sites are likely connected by allosteric cross-talk. 24 rabbit small bowel segments lead to a concentration-dependent increase in the number of toxin 46 receptors and in the sensitivity to the diarrheogenic action of CT 10,13 . CT binds GM1 at the 47 bottom surface of the B-pentamer, which serves as a landing platform on the cell membrane 12 . 48More recently, CT was found to bind histo-blood group antigens (BGAs) at a secondary binding 49 site on the lateral side of the B-pentamer, which had originally been discovered for chimeras of 50 CTB and the homologous Escherichia coli heat-labile enterotoxin (LTB) 18 . Cholera toxin 51 naturally occurs in two variants -classical CT (cCT) and El Tor CT (ET CT), which are 52 produced by the corresponding V. cholerae biotypes 4 . However, since 2001 a new vibrio strain 53 has been observed with characteristics of the El Tor biotype that produces CT with the classical 54 amino acid sequence 19 . The two variants only differ in residues 18 and 47 in the secondary CT 55 binding site (cCT: H18, T47, ET CT: Y18, I47) 4,20 , which is why they have been in the focus of 56 cholera blood group binding studies [21][22][23][24] . Moreover, there is increasing evidence that GM1 is not 57 the only CT receptor and may not even be its main receptor 18,25-31 . 58 Current research shows that fucosylated structures have an important role in cholera 59 intoxication 29,30 . CT binds fucosylated human BGAs merely with millimolar affinity 21-24 , but 60 nevertheless causes blood-group-dependent cellular intoxication 32 . Patients with blood group O 61 are also more likely to get severe cholera symptoms [33][34][35][36] . BGAs are present in the intestine in 62 high concentrations, especially compared to GM1 37 . Most recently, Le x , a BGA precursor 63 expressed on human granulocytes and intestinal cells, has been shown to specifically bind to 64 CTB and was proposed to function as a cellular receptor 30 . Cholera intoxication in mice can be 65 independent of GM1 30 , and fucose-based ...

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Identification of glycoproteins as receptors for cholera toxin in rat intestinal microvillus membranes

Cited by 9 publications

References 0 publications

Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Role of membrane gangliosides in the binding and action of bacterial toxins

Crystal structures reveal that Lewis-x and fucose bind to secondary cholera toxin binding site – in contrast to fucosyl-GM1

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