Abstract
Although globotetraosylceramide (Gb4) is only recognized by a single member of the verotoxin family namely, the pig edema disease toxin (VT2e), removal of the acetyl group from the terminal N-acetyl hexosamine of Gb4 to generate the free amino sugar containing species (aminoGb4) results in the generation of a glycolipid preferentially recognized by all members of the verotoxin family (i.e., VT1, VT2, VT2c, and VT2e). GT3, a site-specific mutant of VT2e, in which Gb4 recognition is lost but Gb3 binding is retained, also binds aminoGb4. We have now compared the binding of VT1, VT2, VT2e, and GT3 to a series of aminoGb4 derivatives using a TLC overlay technique. DimethylaminoGb4 is bound by VT1 and VT2 but not VT2e or GT3; formylaminoGb4 binds all toxins but poorly to VT2 and preferentially VT2e; trifluoroacetylaminoGb4 binds only VT2e and GT3; isopropylaminoGb4 binds VT1 and poorly to VT2; benzylaminoGb4 binds all four toxins. Thus, there is a marked distinction between the permissible amino substitutions for VT1 and VT2e binding. GT3 is a hybrid between these in that, according to the substitution, it behaves similarly either to VT1 or to VT2e. For each species, GT3 does not however, show a hybrid binding between that of VT1 and VT2e. Analysis of the binding as a function of pH shows opposite effects for VT1 and VT2e: decreased pH increases VT1, but decreases VT2e receptor glycolipid binding.
Highlights
Verotoxins (Shiga toxins) are a family of E. coli elaborated subunit toxins involved in microvascular disease [1,2]
Verotoxin 1 (VT1), Verotoxin 2 (VT2), and VT2c are produced by E. coli strains which colonize and affect humans, children, whereas, VT2e is found in strains which infect pigs and is the cause of pig edema disease [3]
VT1 and VT2 are distinguished by the reduced binding of VT2 to Gb3 and isopropylaminoGb4, while VT2e and GT3 are distinguished by the Gb4 and increased formylaminoGb4 binding of VT2e (Table 3)
Summary
Verotoxins (Shiga toxins) are a family of E. coli elaborated subunit toxins involved in microvascular disease [1,2]. VT1, VT2, and VT2c are produced by E. coli strains which colonize and affect humans, children, whereas, VT2e is found in strains which infect pigs and is the cause of pig edema disease [3]. The pentameric B subunit of these toxins bind to a glycolipid receptor, globotriaosylceramide (galα1-4-galβ glucosylceramide, Gb3) [4]. VT2e, binds to globotetraosylceramide (galNAcβ1-3galα1-4-galβ1-4glucosylceramide, Gb4), the homologue in the globo series of glycolipids, in addition to Gb3 [5]. Antibodies against VT1 or toxins of the VT2 series do not cross-neutralize cytotoxicity [6]. VT1 and VT2 are approximately 60% identical, whereas
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