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

J. Biol. Chem., Vol. 282, Issue 10, 7431-7441, March 9, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/10/7431    most recent M610562200v1 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 Collins, C. R. Articles by Blackman, M. J. Search for Related Content PubMed PubMed Citation Articles by Collins, C. R. Articles by Blackman, M. J. Social Bookmarking                      What's this?

Fine Mapping of an Epitope Recognized by an Invasion-inhibitory Monoclonal Antibody on the Malaria Vaccine Candidate Apical Membrane Antigen 1^*

Christine R. Collins, Chrislaine Withers-Martinez, Graham A. Bentley, Adrian H. Batchelor^¶, Alan W. Thomas^||, and Michael J. Blackman¹

From the Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom, the Unité d'Immunologie Structurale, CNRS URA 2185, Département de Biologie Structurale & Chimie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris cedex 15, France, the ^¶School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, and the ^||Biomedical Primate Research Centre, Lange Kleiweg 139, 2280 GH Rijswijk, The Netherlands

Antibodies that inhibit red blood cell invasion by the Plasmodium merozoite block the erythrocytic cycle responsible for clinical malaria. The invasion-inhibitory monoclonal antibody (mAb) 4G2 recognizes a conserved epitope in the ectodomain of the essential Plasmodium falciparum microneme protein and vaccine candidate, apical membrane antigen 1 (PfAMA1). Here we demonstrate that purified Fab fragments of 4G2 inhibit invasion markedly more efficiently than the intact mAb, suggesting that the invasion-inhibitory activity of this mAb is not due solely to steric effects and that the epitope lies within a functionally critical region of the molecule. We have taken advantage of a synthetic gene encoding a modified form of PfAMA1, and existing x-ray crystal structure data, to fully characterize this epitope. We first validate the gene by demonstrating that it fully complements the function of the authentic gene in P. falciparum.We then use it to identify a group of residues within the previously described domain II loop of PfAMA1 that are critical for recognition by mAb 4G2 and demonstrate that the epitope lies exclusively within this loop with no contributions from residues in other domains of the molecule. This is the first complete characterization of a conserved invasion-inhibitory epitope on PfAMA1. Our results will aid in the design of subunit vaccines designed to generate a broadly effective, focused anti-PfAMA1 protective immune response and may help elucidate the function of PfAMA1.

Received for publication, November 14, 2006 , and in revised form, December 18, 2006.

^* This work was supported by the Medical Research Council, United Kingdom, by the European Commission FP6 Network of Excellence BioMalPar, and by contracts with the European Commission (Grants QLK2-CT-2001-01302 and QLK2-CT-2002-01197). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed. Tel.: 44-208-816-2127; Fax: 44-208-816-2730; E-mail: mblackm{at}nimr.mrc.ac.uk.

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

This article has been cited by other articles:

				S. K. Pierce and L. H. Miller World Malaria Day 2009: What Malaria Knows about the Immune System That Immunologists Still Do Not J. Immunol., May 1, 2009; 182(9): 5171 - 5177. [Abstract] [Full Text] [PDF]

				K. S. Harris, J. L. Casey, A. M. Coley, J. A. Karas, J. K. Sabo, Y. Y. Tan, O. Dolezal, R. S. Norton, A. B. Hughes, D. Scanlon, et al. Rapid Optimization of a Peptide Inhibitor of Malaria Parasite Invasion by Comprehensive N-Methyl Scanning J. Biol. Chem., April 3, 2009; 284(14): 9361 - 9371. [Abstract] [Full Text] [PDF]

				M. M. Lynch, A. Cernetich-Ott, W. P. Weidanz, and J. M. Burns Jr. Prediction of Merozoite Surface Protein 1 and Apical Membrane Antigen 1 Vaccine Efficacies against Plasmodium chabaudi Malaria Based on Prechallenge Antibody Responses Clin. Vaccine Immunol., March 1, 2009; 16(3): 293 - 302. [Abstract] [Full Text] [PDF]

				S. Dutta, S. Y. Lee, A. H. Batchelor, and D. E. Lanar Structural basis of antigenic escape of a malaria vaccine candidate PNAS, July 24, 2007; 104(30): 12488 - 12493. [Abstract] [Full Text] [PDF]