A mutant cholera toxin B subunit that binds GM1-ganglioside but lacks immunomodulatory or toxic activity

被引:84
作者
Aman, AT
Fraser, S
Merritt, EA
Rodigherio, C
Kenny, M
Ahn, M
Hol, WGJ
Williams, NA
Lencer, WI
Hirst, TR [1 ]
机构
[1] Univ Bristol, Dept Pathol & Microbiol, Bristol BS8 1TD, Avon, England
[2] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA
[3] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA
[4] Childrens Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02115 USA
关键词
D O I
10.1073/pnas.161273098
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
CM1-ganglioside receptor binding by the B subunit of cholera toxin (CtxB) is widely accepted to initiate toxin action by triggering uptake and delivery of the toxin A subunit into cells. More recently, GM1 binding by isolated CtxB, or the related B subunit of Escherichia coli heat-labile enterotoxin (EtxB), has been found to modulate leukocyte function, resulting in the down-regulation of proinflammatory immune responses that cause autoimmune disorders such as rheumatoid arthritis and diabetes. Here, we demonstrate that GM1 binding, contrary to expectation, is not sufficient to initiate toxin action. We report the engineering and crystallographic structure of a mutant cholera toxin, with a His to Ala substitution in the B subunit at position 57. Whereas the mutant retained pentameric stability and high affinity binding to GM1-ganglioside, it had lost its immunomodulatory activity and, when part of the holotoxin complex, exhibited ablated toxicity. The implications of these findings on the mode of action of cholera toxin are discussed.
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页码:8536 / 8541
页数:6
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