the tip of the four n-terminal α-helices of clostridium sordellii lethal toxin contains the interaction site with membrane phosphatidylserine facilitating small gtpases glucosylation

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ID: 188189
2016
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Abstract
Clostridium sordellii lethal toxin (TcsL) is a powerful virulence factor responsible for severe toxic shock in man and animals. TcsL belongs to the large clostridial glucosylating toxin (LCGT) family which inactivates small GTPases by glucosylation with uridine-diphosphate (UDP)-glucose as a cofactor. Notably, TcsL modifies Rac and Ras GTPases, leading to drastic alteration of the actin cytoskeleton and cell viability. TcsL enters cells via receptor-mediated endocytosis and delivers the N-terminal glucosylating domain (TcsL-cat) into the cytosol. TcsL-cat was found to preferentially bind to phosphatidylserine (PS)-containing membranes and to increase the glucosylation of Rac anchored to the lipid membrane. We have previously reported that the N-terminal four helical bundle structure (1–93 domain) recognizes a broad range of lipids, but that TcsL-cat specifically binds to PS and phosphatidic acid. Here, we show using mutagenesis that the PS binding site is localized on the tip of the four-helix bundle which is rich in positively-charged amino acids. Residues Y14, V15, F17, and R18 on loop 1, between helices 1 and 2, in coordination with R68 from loop 3, between helices 3 and 4, form a pocket which accommodates L-serine. The functional PS-binding site is required for TcsL-cat binding to the plasma membrane and subsequent cytotoxicity. TcsL-cat binding to PS facilitates a high enzymatic activity towards membrane-anchored Ras by about three orders of magnitude as compared to Ras in solution. The PS-binding site is conserved in LCGTs, which likely retain a common mechanism of binding to the membrane for their full activity towards membrane-bound GTPases.
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chavez2016toxinsthe Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Carolina Varela Chavez, Georges Michel Haustant, Bruno Baron, Patrick England, Alexandre Chenal, Serge Pauillac, Arnaud Blondel, Michel-Robert Popoff
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Journal matec web of conferences
Year 2016
DOI
10.3390/toxins8040090
URL
http://www.mdpi.com/2072-6651/8/4/90
Keywords
clostridium difficile

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