期刊
BIOCHEMISTRY
卷 49, 期 28, 页码 5954-5967出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi100474z
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资金
- National Institutes of Health [R01 AI 023695, U01 AI 075498]
- National Science Foundation [CHE-0845005]
- National Institute of General Medical Sciences [GM62116]
Binding of pertussis toxin (PTx) was examined by a glycan microarray; 53 positive hits fell into four general groups. One group represents sialylated biantennary compounds with an N-glycan core terminating in alpha 2-6-linked sialic acid. The second group consists of multiantennary compounds with a canonical N-glycan core, but lacking terminal sialic acids, which represents a departure from the previous understanding of PTx binding to N-glycans. The third group consists of Neu5Ac alpha 2-3(lactose or N-acetyl-lactosamine) forms that lack the branched mannose core found in N-glycans; thus, their presentation is more similar to that of O-linked glycans and glycolipids. The fourth group of compounds consists of Neu5Ac alpha 2-8Neu5Ac alpha 2-8Neu5Ac, which is seen in the c series gangliosides and some N-glycans. Quantitative analysis by surface plasmon resonance of the relative affinities of PTx for terminal Neu5Ac alpha 2-3 versus Neu5Ac alpha 2-6, as well as the affinities for the trisaccharide Neu5Ac alpha 2-8Neu5Ac alpha 2-8Neu5Ac versus disaccharide, revealed identical global affinities, even though the amount of bound glycan varied by 4-5-fold. These studies suggest that the conformational space occupied by a glycan can play an important role in binding, independent of affinity. Characterization of N-terminal and C-terminal binding sites on the S2 and S3 subunits by mutational analysis revealed that binding to all sialylated compounds was mediated by the C-terminal binding sites, and binding to nonsialylated N-linked glycans is mediated by the N-terminal sites present on both the S2 and S3 subunits. A detailed understanding of the glycans recognized by pertussis toxin is essential to understanding which cells are targeted in clinical disease.
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