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Infection and Immunity, October 2005, p. 6981-6989, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6981-6989.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Binding Hot Spot for Invasion Inhibitory Molecules on Plasmodium falciparum Apical Membrane Antigen 1{dagger}

Karen S. Harris,1,3 Joanne L. Casey,1,3 Andrew M. Coley,1,3,4 Rosella Masciantonio,1,4 Jennifer K. Sabo,2 David W. Keizer,2 Erinna F. Lee,2 Andrew McMahon,5 Raymond S. Norton,2 Robin F. Anders,1,4 and Michael Foley1,3,4*

Cooperative Research Centre for Diagnostics,3 Cooperative Research Centre for Vaccine Technology,4 Department of Biochemistry, La Trobe University, Victoria 3086, Australia,1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia,2 Department of Veterinary Science, The University of Melbourne, Victoria 3010, Australia5

Received 18 May 2005/ Accepted 26 May 2005

Apical membrane antigen 1 (AMA1) is expressed in schizont-stage malaria parasites and sporozoites and is thought to be involved in the invasion of host red blood cells. AMA1 is an important vaccine candidate, as immunization with this antigen induces a protective immune response in rodent and monkey models of human malaria. Additionally, anti-AMA1 polyclonal and monoclonal antibodies inhibit parasite invasion in vitro. We have isolated a 20-residue peptide (R1) from a random peptide library that binds to native AMA1 as expressed by Plasmodium falciparum parasites. Binding of R1 peptide is dependent on AMA1 having the proper conformation, is strain specific, and results in the inhibition of merozoite invasion of host erythrocytes. The solution structure of R1, as determined by nuclear magnetic resonance spectroscopy, contains two structured regions, both involving turns, but the first region, encompassing residues 5 to 10, is hydrophobic and the second, at residues 13 to 17, is more polar. Several lines of evidence reveal that R1 targets a "hot spot" on the AMA1 surface that is also recognized by other peptides and monoclonal antibodies that have previously been shown to inhibit merozoite invasion. The functional consequence of binding to this region by a variety of molecules is the inhibition of merozoite invasion into host erythrocytes. The interaction between these peptides and AMA1 may further our understanding of the molecular mechanisms of invasion by identifying critical functional regions of AMA1 and aid in the development of novel antimalarial strategies.

* Corresponding author. Mailing address: Department of Biochemistry, La Trobe University, Victoria 3086, Australia. Phone: 61 3 94792158. Fax: 61 3 94792467. E-mail: m.foley{at}latrobe.edu.au.

{dagger} Supplementary material for this article may be found at http://iai.asm.org.

Editor: W. A. Petri, Jr.

Infection and Immunity, October 2005, p. 6981-6989, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6981-6989.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Harris, K. S., Casey, J. L., Coley, A. M., Karas, J. A., Sabo, J. K., Tan, Y. Y., Dolezal, O., Norton, R. S., Hughes, A. B., Scanlon, D., Foley, M. (2009). Rapid Optimization of a Peptide Inhibitor of Malaria Parasite Invasion by Comprehensive N-Methyl Scanning. J. Biol. Chem. 284: 9361-9371 [Abstract] [Full Text]  
  • Coley, A. M., Parisi, K., Masciantonio, R., Hoeck, J., Casey, J. L., Murphy, V. J., Harris, K. S., Batchelor, A. H., Anders, R. F., Foley, M. (2006). The Most Polymorphic Residue on Plasmodium falciparum Apical Membrane Antigen 1 Determines Binding of an Invasion-Inhibitory Antibody.. Infect. Immun. 74: 2628-2636 [Abstract] [Full Text]  


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