Structure and inter-domain interactions of domain II from the blood-stage malarial protein, apical membrane antigen 1
Details
Publication Year 2005-07-22, Volume 350, Issue #4, Page 641-656
Journal Title
JOURNAL OF MOLECULAR BIOLOGY
Publication Type
Journal Article
Abstract
The malarial surface antigen apical membrane antigen (AMA1), from Plasmodium falciparum, is a leading candidate for inclusion in a vaccine against malaria. AMA1 is synthesised by mature blood-stages of the parasite and is located initially in the apical organelles of the merozoite. Prior to merozoite invasion of host erythrocytes, it is processed into a 66 kDa type 1 integral membrane protein on the merozoite surface. The pattern of disulphide bonds in AMA1 has been the basis for separation of the ectodomain into three domains, with three, two and three disulphide bonds, respectively. We have determined the solution structure of a 16 kDa construct corresponding to the putative second domain of AMA1. While circular dichroism and hydrodynamic data were consistent with a folded structure for domain II, its NMR spectra were characterised by broad lines and significant peak overlap, more typical of a molten globule. Consistent with this, domain II bound the fluorescent dye 8-anilino-1-naphthalene sulphonate (ANS). We have nonetheless determined a structure, which defines the secondary structure elements and global fold. The two disulphide bonds link the N and C-terminal regions of the molecule, which come together to form a four-stranded P-sheet linked to a short helix. A long loop linking the N and C-terminal regions contains four other a-helices, the locations of which are not fixed relative to the beta-sheet core, even though they are well-defined locally. Very recently this region of domain II has been shown to contain the epitope recognised by the invasion-inhibitory antibody 4G2, even though it does not contain any of the polymorphisms that are regarded as having arisen in response to the pressure of immune recognition. (c) 2005 Elsevier Ltd. All rights reserved.
Publisher
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
Keywords
MOLTEN GLOBULE STATE; PLASMODIUM-FALCIPARUM MEROZOITES; NUCLEAR-MAGNETIC-RESONANCE; VACCINE CANDIDATE; SECONDARY STRUCTURE; UNFOLDED PROTEINS; CHEMICAL-SHIFT; ERYTHROCYTE INVASION; SELF-ASSOCIATION; HUMAN-ANTIBODIES
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Creation Date: 2005-07-22 12:00:00
Last Modified: 0001-01-01 12:00:00
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