HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 22, 21194-21201, June 3, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/22/21194    most recent M412656200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Méré, J. Articles by Beaumelle, B. Search for Related Content PubMed PubMed Citation Articles by Méré, J. Articles by Beaumelle, B. Social Bookmarking                      What's this?

Acid-triggered Membrane Insertion of Pseudomonas Exotoxin A Involves an Original Mechanism Based on pH-regulated Tryptophan Exposure^*

Jocelyn Méré, Juliette Morlon-Guyot, Anne Bonhoure, Laurent Chiche, and Bruno Beaumelle¶

From the Unite Mixte de Recherche 5539 CNRS, Case 107, Département Biologie-Santé, Université Montpellier II, 34095 Montpellier and Centre de Biochimie Structurale, Unite Mixte de Recherche 5048 CNRS INSERM U554, Faculté de Pharmacie, 34093 Montpellier, France

Exposure to low endosomal pH during internalization of Pseudomonas exotoxin A (PE) triggers membrane insertion of its translocation domain. This process is a prerequisite for PE translocation to the cytosol where it inactivates protein synthesis. Although hydrophobic helices enable membrane insertion of related bacterial toxins such as diphtheria toxin, the PE translocation domain is devoid of hydrophobic stretches and the structural features triggering acid-induced membrane insertion of PE are not known. Here we have identified a molecular device that enables PE membrane insertion. This process is promoted by exposure of a key tryptophan residue. At neutral pH, this Trp is buried in a hydrophobic pocket closed by the smallest -helix of the translocation domain. Upon acidification, protonation of the Asp that is the N-cap residue of the helix leads to its destabilization, enabling Trp side chain insertion into the endosome membrane. This tryptophan-based membrane insertion system is surprisingly similar to the membrane-anchoring mechanism of human annexin-V and could be used by other proteins as well.

Received for publication, November 9, 2004 , and in revised form, March 29, 2005.

^* This work was supported by grants from the Association pour la Recherche sur le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 33-467-14-33-98; Fax: 33-467-14-42-86; E-mail: beaumel{at}univ-montp2.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Morlon-Guyot, J. Mere, A. Bonhoure, and B. Beaumelle Processing of Pseudomonas aeruginosa Exotoxin A Is Dispensable for Cell Intoxication Infect. Immun., July 1, 2009; 77(7): 3090 - 3099. [Abstract] [Full Text] [PDF]

				J. E. Weldon, L. Xiang, O. Chertov, I. Margulies, R. J. Kreitman, D. J. FitzGerald, and I. Pastan A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity Blood, April 16, 2009; 113(16): 3792 - 3800. [Abstract] [Full Text] [PDF]

				A. Perier, A. Chassaing, S. Raffestin, S. Pichard, M. Masella, A. Menez, V. Forge, A. Chenal, and D. Gillet Concerted Protonation of Key Histidines Triggers Membrane Interaction of the Diphtheria Toxin T Domain J. Biol. Chem., August 17, 2007; 282(33): 24239 - 24245. [Abstract] [Full Text] [PDF]

				M. Rodriguez, G. Torrent, M. Bosch, F. Rayne, J.-F. Dubremetz, M. Ribo, A. Benito, M. Vilanova, and B. Beaumelle Intracellular pathway of Onconase that enables its delivery to the cytosol J. Cell Sci., April 15, 2007; 120(8): 1405 - 1411. [Abstract] [Full Text] [PDF]

				J. Srivastava, D. L. Barber, and M. P. Jacobson Intracellular pH Sensors: Design Principles and Functional Significance Physiology, February 1, 2007; 22(1): 30 - 39. [Abstract] [Full Text] [PDF]