A partially structured region of a largely unstructured protein, Plasmodium falciparum merozoite surface protein 2 (MSP2), forms amyloid-like fibrils.
Merozoite surface protein 2 (MSP2) from the human malaria parasite Plasmodium falciparum is expressed as a GPI-anchored protein on the merozoite surface. It has been implicated in the process of erythrocyte invasion and is a leading vaccine candidate. MSP2 is an intrinsically unstructured protein (IUP), and recombinant MSP2 forms amyloid-like fibrils upon storage. We have examined synthetic peptides corresponding to sequences in the conserved N-terminal region of MSP2 for the presence of local structure and the ability to form fibrils related to those formed by full-length MSP2. In a 25-residue peptide corresponding to the entire N-terminal region of mature MSP2, structures calculated from NMR data show the presence of nascent helical and turn-like structures. An 8-residue peptide from the central region of the N-terminal domain (residues 8-15) also formed a turn-like structure. Both peptides formed fibrils that were similar but not identical to the amyloid-like fibrils formed by full-length MSP2. Notably, the fibrils formed by the peptides bound both Congo Red and Thioflavin T, whereas the fibrils formed by full-length MSP2 bound only Congo Red. The propensity of peptides from the N-terminal conserved region of MSP2 to form amyloid-like fibrils makes it likely that this region contributes to fibril formation by the full-length protein. Thus, in contrast to the more common pathway of amyloid formation by structured proteins, which proceeds via partially unfolded intermediates that then undergo beta-aggregation, MSP2 is an example of a largely unstructured protein with at least one small structured region that has an important role in fibril formation.
Yang
Xiaodong
X
The Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Australia.
Adda
Christopher G
CG
Keizer
David W
DW
Murphy
Vince J
VJ
Rizkalla
Michael M
MM
Perugini
Matthew A
MA
Jackson
David C
DC
Anders
Robin F
RF
Norton
Raymond S
RS
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry*; D002942:Circular Dichroism / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008854:Microscopy, Electron / Q000379:methods; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000737:chemistry*; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry
D000682:Amyloid; D000953:Antigens, Protozoan; D010446:Peptide Fragments; D015800:Protozoan Proteins; D012996:Solutions; C065974:merozoite surface protein 2, Plasmodium