Solution conformation, backbone dynamics and lipid interactions of the intrinsically unstructured malaria surface protein MSP2

Zhang, XC; Perugini, MA; Yao, S; Adda, CG; Murphy, VJ; Low, A; Anders, RF; Norton, RS

Author(s): Zhang, XC; Perugini, MA; Yao, S; Adda, CG; Murphy, VJ; Low, A; Anders, RF; Norton, RS;
Details: Publication Year 2008-05-23,Volume 379,Issue #1,Page 105-121
Journal Title: JOURNAL OF MOLECULAR BIOLOGY
Publication Type: Journal Article
Abstract: Merozoite surface protein 2 (MSP2), one of the most abundant proteins on the surface of the merozoite stage of Plasmodium falciparum, is a potential component of a malaria vaccine, having shown some efficacy in a clinical trial in Papua New Guinea. MSP2 is a GPI-anchored protein consisting of conserved N- and C-terminal domains and a variable central region. Previous studies have shown that it is an intrinsically unstructured protein with a high propensity for fibril formation, in which the conserved N-terminal domain has a key role. Secondary structure predictions suggest that MSP2 contains long stretches of random coil with very little alpha-helix or beta-strand. Circular dichroism spectroscopy confirms this prediction under physiological conditions (pH 7.4) and in more acidic solutions (pH 6.2 and 3.4). Pulsed field gradient NMR diffusion measurements showed that MSP2 under physiological conditions has a large effective hydrodynamic radius consistent with an intrinsic pre-molten globule state, as defined by Uversky. This was supported by sedimentation velocity studies in the analytical ultracentrifuge. NMR resonance assignments have been obtained for FC27 MSP2, allowing the residual secondary structure and backbone dynamics to be defined. There is some motional restriction in the conserved C-terminal region in the vicinity of an intramolecular disulfide bond. Two other regions show motional restrictions, both of which display helical structure propensities. One of these helical regions is within the conserved N-terminal domain, which adopts essentially the same conformation in full-length MSP2 as in corresponding peptide fragments. We see no evidence of long-range interactions in the full-length protein. MSP2 associates with lipid micelles, but predominantly through the N-terminal region rather than the C terminus, which is GPI-anchored to the membrane in the parasite. (C) 2008 Elsevier Ltd. All rights reserved.
Publisher: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Keywords: SECONDARY STRUCTURE PREDICTION; PLASMODIUM-FALCIPARUM MALARIA; NMR CHEMICAL-SHIFTS; N-TERMINAL DOMAIN; ALPHA-SYNUCLEIN; STRUCTURAL-CHARACTERIZATION; UNFOLDED PROTEINS; SELF-ASSOCIATION; FIBRIL FORMATION; FOLDED PROTEINS
Publisher's Version: https://doi.org/10.1016/j.jmb.2008.03.039
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2008-05-23 12:00:00