Role of the helical structure of the N-terminal region of Plasmodium falciparum merozoite surface protein 2 in fibril formation and membrane interaction.
Merozoite surface protein 2 (MSP2), an abundant glycosylphosphatidylinositol-anchored protein on the surface of Plasmodium falciparum merozoites, is a promising malaria vaccine candidate. MSP2 is intrinsically disordered and forms amyloid-like fibrils in solution under physiological conditions. The 25 N-terminal residues (MSP2(1-25)) play an important role in both fibril formation and membrane binding of the full-length protein. In this study, the fibril formation and solution structure of MSP2(1-25) in the membrane mimetic solvents sodium dodecyl sulfate (SDS), dodecylphosphocholine (DPC), and trifluoroethanol (TFE) have been investigated by transmission electronic microscopy, turbidity, thioflavin T fluorescence, circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy. Turbidity data showed that the aggregation of MSP2(1-25) was suppressed in the presence of membrane mimetic solvents. CD spectra indicated that helical structure in MSP2(1-25) was stabilized in SDS and DPC micelles and in high concentrations of TFE. The structure of MSP2(1-25) in 50% aqueous TFE, determined using NMR, showed that the peptide formed an amphipathic helix encompassing residues 10-24. Low concentrations of TFE favored partially folded helical conformations, as demonstrated by CD and NMR, and promoted MSP2(1-25) fibril formation. Our data suggest that partially folded helical conformations of the N-terminal region of MSP2 are on the pathway to amyloid fibril formation, while higher degrees of helical structure stabilized by high concentrations of TFE or membrane mimetics suppress self-association and thus inhibit fibril formation. The roles of the induced helical conformations in membrane interactions are also discussed.
School of Life Sciences, Anhui University, Hefei, Anhui 230039, P R China. turenzh@ahu.edu.cn
Xuecheng
X
Zhang
Christopher G
CG
Adda
Andrew
A
Low
Jiahai
J
Zhang
Wen
W
Zhang
Hongbin
H
Sun
Xiaoming
X
Tu
Robin F
RF
Anders
Raymond S
RS
Norton
D000682:Amyloid / Q000737:chemistry; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008823:Micelles; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D013053:Spectrophotometry / Q000379:methods; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry
D000682:Amyloid; D000953:Antigens, Protozoan; D052160:Benzothiazoles; D008051:Lipid Bilayers; D008823:Micelles; D015800:Protozoan Proteins; D013844:Thiazoles; C065974:merozoite surface protein 2, Plasmodium; C009462:thioflavin T