| Domain mapping of a claudin-4 modulator, the C-terminal region of C-terminal fragment of Clostridium perfringens enterotoxin, by site-directed mutagenesis. | |
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MedLine Citation:
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PMID: 18342294 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) is a modulator of claudin-4. We previously found that upon deletion of the C-terminal 16 amino acids, C-CPE lost its ability to modulate claudin-4. Tyrosine residues in the 16 amino acids were involved in the modulation of claudin-4. In the present study, we performed functional domain mapping of the 16-amino acid region of C-CPE by replacing individual amino acids with alanine. To evaluate the ability of the alanine-substituted mutants to interact with claudin-4, we carried out a competition analysis using claudin-4-targeting protein synthesis inhibitory factor. We found that Tyr306Ala, Tyr310Ala, Tyr312Ala, and Leu315Ala mutants had reduced binding to claudin-4 compared to C-CPE. Next, we investigated effects of each alanine-substituted mutant on the TJ-barrier function in Caco-2 monolayer cells. The TJ-disrupting activity of C-CPE was reduced by the Tyr306Ala and Leu315Ala substitutions. Enhancement of rat jejunal absorption was also decreased by each of these mutations. The double mutant Tyr306Ala/Leu315Ala lost the ability to interact with claudin-4, modulate TJ-barrier function, and enhance jejunal absorption. These data indicate that Tyr306 and Leu315 are key residues in the modulation of claudin-4 by C-CPE. This information should be useful for the development of a novel claudin modulator based on C-CPE. |
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Authors:
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Azusa Takahashi; Eriko Komiya; Hideki Kakutani; Takeshi Yoshida; Makiko Fujii; Yasuhiko Horiguchi; Hiroyuki Mizuguchi; Yasuo Tsutsumi; Shin-ichi Tsunoda; Naoya Koizumi; Katsuhiro Isoda; Kiyohito Yagi; Yoshiteru Watanabe; Masuo Kondoh |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-01-05 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 75 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2008 Apr |
Date Detail:
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Created Date: 2008-03-31 Completed Date: 2008-04-22 Revised Date: 2009-05-21 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1639-48 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acids
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chemistry,
genetics,
metabolism Animals Caco-2 Cells Cell Line Enterotoxins / chemistry*, genetics, pharmacology Humans Jejunum / metabolism Male Membrane Proteins / metabolism* Mice Mutagenesis, Site-Directed Protein Structure, Tertiary Rats Rats, Wistar Tight Junctions / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/Enterotoxins; 0/Membrane Proteins; 0/claudin 4; 0/enterotoxin, Clostridium |
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