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Structural characteristics for biological activity of heat-stable enterotoxin produced by enterotoxigenic Escherichia coli: X-ray crystallography of weakly toxic and nontoxic analogs.

Sato T, Ozaki H, Hata Y, Kitagawa Y, Katsube Y, Shimonishi Y
Biochemistry 33 8641-50 (1994)
Cited: 24 times
EuropePMC logo PMID: 8038153

Abstract

Heat-stable enterotoxin (ST) produced by a pathogenic strain of Escherichia coli exerts its function by binding to a membrane-bound guanylyl cyclase on intestinal epithelial cell membranes, which in turn catalyzes the production of cyclic GMP as a second messenger in the cells. To elucidate the structural requirements for the biological activities of ST, we synthesized [Mpr5,Gly13]STp(5-17) and [Mpr5,Leu13]STp(5-17), which are weakly toxic and nontoxic analogs of STp, in which the toxic domain consists of the sequence from Cys at position 5 to Cys at position 17. In these analogs, Cys at position 5 is replaced by Mpr (beta-mercaptopropionic acid) and Ala at position 13 by Gly and Leu, respectively. We examined these analogs by X-ray diffraction analysis using direct methods and refined the structures to crystallographic R factors of 7.3% and 6.6% using 5492 and 5122 data, respectively, observed > 3 sigma (Fo) with a resolution of 0.89 A. These peptides have a right-handed spiral structure consisting of three structural segments: an N-terminal 3(10) helix, a central type I beta-turn, and a C-terminal type II beta-turn. These structures show minor differences from that of [Mpr5]STp(5-17), the fully toxic analog of heat-stable enterotoxin [Ozaki et al. (1991) J. Biol. Chem. 266, 5934-5941], suggesting that the decrease and loss of the biological activities of [Mpr5,Gly13]STp(5-17) and [Mpr5,Leu13]STp(5-17), respectively, are not caused by structural changes but are associated with the direct interaction of Ala13 with the receptor protein. Careful comparison of these structures in crystalline states revealed that ST has the following structural characteristics: (i) inherent flexibility at the junctions of the three segments and in the central segment, which includes the putative receptor-binding residues, Ala13, (ii) a specific hydrophobic character around the central segment, and (iii) an unexpected C-terminal folding similar to those of functionally unrelated peptides that are known to be ionophores.

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Reviews citing this publication (7)

  1. Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion. Sears CL, Kaper JB. Microbiol Rev 60 167-215 (1996)
  2. Occurrence, distribution, and associations of O and H serogroups, colonization factor antigens, and toxins of enterotoxigenic Escherichia coli. Wolf MK. Clin Microbiol Rev 10 569-584 (1997)
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Articles citing this publication (6)

  1. Receptor guanylyl cyclase C (GC-C): regulation and signal transduction. Basu N, Arshad N, Visweswariah SS. Mol Cell Biochem 334 67-80 (2010)
  2. Heat-labile- and heat-stable-toxoid fusions (LTR₁₉₂G-STaP₁₃F) of human enterotoxigenic Escherichia coli elicit neutralizing antitoxin antibodies. Liu M, Ruan X, Zhang C, Lawson SR, Knudsen DE, Nataro JP, Robertson DC, Zhang W. Infect Immun 79 4002-4009 (2011)
  3. Contribution of defined amino acid residues to the immunogenicity of recombinant Escherichia coli heat-stable enterotoxin fusion proteins. Batisson I, Der Vartanian M. FEMS Microbiol Lett 192 223-229 (2000)
  4. Evidence for stimulation of the inositol triphosphate-Ca2+ signalling system in rat enterocytes by heat stable enterotoxin of Escherichia coli. Chaudhuri AG, Ganguly U. Biochim Biophys Acta 1267 131-133 (1995)
  5. Structural features of Escherichia coli heat-stable enterotoxin that activates membrane-associated guanylyl cyclase. Sato T, Shimonishi Y. J Pept Res 63 200-206 (2004)
  6. Charges, hydrogen bonds, and correlated motions in the 1 A resolution refined structure of the mating pheromone Er-1 from Euplotes raikovi. Anderson DH, Weiss MS, Eisenberg D. J Mol Biol 273 479-500 (1997)


Related citations provided by authors (4)

  1. Semi-Preparative Purification and Crystallization of Synthetic Analogs of Heat-Stable Enterotoxin of Enterotoxigenic Escherichia Coli. Sato T, Ito H, Takeda Y, Shimonishi Y Bull. Chem. Soc. Jpn. 65 938- (1992)
  2. Molecular Structure of the Toxic Domain of Heat-Stable Enterotoxin Produced by a Pathogenic Strain of Escherichia Coli. Ozaki H, Sato T, Kubota H, Hata Y, Katsube Y, Shimonishi Y J. Biol. Chem. 266 5934- (1991)
  3. Structure-Activity Relationship of Escherichia Coli Heat-Stable Enterotoxin: Role of Ala Residue at Position 14 in Toxin-Receptor Interaction. Yamasaki S, Sato T, Hidaka Y, Ozaki H, Ito H, Hirayama T, Takeda Y, Sugimura T, Tai A, Shimonishi Y Bull. Chem. Soc. Jpn. 63 2063- (1990)
  4. Essential structure for full enterotoxigenic activity of heat-stable enterotoxin produced by enterotoxigenic Escherichia coli.. Yoshimura S, Ikemura H, Watanabe H, Aimoto S, Shimonishi Y, Hara S, Takeda T, Miwatani T, Takeda Y FEBS Lett 181 138-42 (1985)

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