期刊
NATURE MICROBIOLOGY
卷 1, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NMICROBIOL.2015.2
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资金
- NIAID of the National Institutes of Health [R01AI095755]
- NIGMS [R01GM042569]
- US DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- US DOE, Office of Science, Office of Basic Energy Sciences [DE-AC02-98CH10886]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI095755] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [P30EB009998] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM065086, R01GM042569] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX002943] Funding Source: NIH RePORTER
Clostridium difficile infection is the leading cause of hospital-acquired diarrhoea and pseudomembranous colitis. Disease is mediated by the actions of two toxins, TcdA and TcdB, which cause the diarrhoea, as well as inflammation and necrosis within the colon(1,2). The toxins are large (308 and 270 kDa, respectively), homologous (47% amino acid identity) glucosyl-transferases that target small GTPases within the host(3,4). The multidomain toxins enter cells by receptor-mediated endocytosis and, upon exposure to the low pH of the endosome, insert into and deliver two enzymatic domains across the membrane. Eukaryotic inositol-hexakisphosphate (InsP6) binds an autoprocessing domain to activate a proteolysis event that releases the N-terminal glucosyltransferase domain into the cytosol. Here, we report the crystal structure of a 1,832-amino-acid fragment of TcdA (TcdA(1832)), which reveals a requirement for zinc in the mechanism of toxin autoprocessing and an extended delivery domain that serves as a scaffold for the hydrophobic alpha-helices involved in pH-dependent pore formation. A surface loop of the delivery domain whose sequence is strictly conserved among all large clostridial toxins is shown to be functionally important, and is highlighted for future efforts in the development of vaccines and novel therapeutics.
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