Identification of key residues involved in fibril formation by the conserved N-terminal region of Plasmodium falciparum merozoite surface protein 2 (MSP2)

Yang, XD; Adda, CG; MacRaild, CA; Low, A; Zhang, XC; Zeng, WG; Jackson, DC; Anders, RF; Norton, RS

Author(s): Yang, XD; Adda, CG; MacRaild, CA; Low, A; Zhang, XC; Zeng, WG; Jackson, DC; Anders, RF; Norton, RS;
Details: Publication Year 2010-10,Volume 92,Issue #10,Page 1287-1295
Journal Title: BIOCHIMIE
Publication Type: Journal Article
Abstract: Merozoite surface protein 2 (MSP2) from the human malaria parasite Plasmodium falciparum is expressed as a GPI-anchored protein on the merozoite surface. MSP2 is assumed to have a role in erythrocyte invasion and is a leading vaccine candidate. Recombinant MSP2 forms amyloid-like fibrils upon storage, as do peptides corresponding to sequences in the conserved N-terminal region, which constitutes the structural core of fibrils formed by full-length MSP2. We have investigated the roles of individual residues in fibril formation and local ordered structure in two peptides, a recombinant 25-residue peptide corresponding to the entire N-terminal domain of mature MSP2 and an 8-residue peptide from the central region of this domain (residues 8-15). Both peptides formed fibrils that were similar to amyloid-like fibrils formed by full-length MSP2. Phe11 and Ile12 have important roles both in stabilising local structure in these peptides and promoting fibril formation; the F11A and I12A mutants of MSP2(8-15) were essentially unstructured in solution and fibril formation at pH 7.4 and 4.7 was markedly retarded. The T10A mutant showed intermediate behaviour, having a less well defined structure than wild-type and slower fibril formation at pH 7.4. The mutation of Phe11 and Ile12 in MSP2(1-25) significantly retarded but did not abolish fibril formation, indicating that these residues also play a key role in fibril formation by the entire N-terminal conserved region. These mutations had little effect on the aggregation of full-length MSP2, however, suggesting that regions outside the conserved N-terminus have unanticipated importance for fibril formation in the full-length protein. (C) 2010 Elsevier Masson SAS. All rights reserved.
Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Keywords: AMYLOID-LIKE FIBRILS; MEMBRANE-PROTEINS; NMR-SPECTROSCOPY; SELF-ASSOCIATION; MALARIA VACCINE; POLYMORPHISM; DIVERSITY; ANTIGEN-2; DIFFUSION; DYNAMICS
Publisher's Version: https://doi.org/10.1016/j.biochi.2010.06.001
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Creation Date: 2010-10-01 12:00:00