Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2.
The abundant Plasmodium falciparum merozoite surface protein MSP2, a potential malaria vaccine candidate, is an intrinsically disordered protein with some nascent secondary structure present in its conserved N-terminal region. This relatively ordered region has been implicated in both membrane interactions and amyloid-like aggregation of the protein, while the significance of the flanking-disordered region is unclear. In this study, we show that aggregation of the N-terminal conserved region of MSP2 is influenced in a length- and sequence-dependent fashion by the disordered central variable sequences. Intriguingly, MSP2 peptides containing the conserved region and the first five residues of the variable disordered regions aggregated more rapidly than a peptide corresponding to the conserved region alone. In contrast, MSP2 peptides extending 8 or 12 residues into the disordered region aggregated more slowly, consistent with the expected inhibitory effect of flanking-disordered sequences on the aggregation of amyloidogenic ordered sequences. Computational analyses indicated that the helical propensity of the ordered region of MSP2 was modulated by the adjacent disordered five residues in a sequence-dependent manner. Nuclear magnetic resonance and circular dichroism spectroscopic studies with synthetic peptides confirmed the computational predictions, emphasizing the correlation between aggregation propensity and conformation of the ordered region and the effects thereon of the adjacent disordered region. These results show that the effects of flanking-disordered sequences on a more ordered sequence may include enhancement of aggregation through modulation of the conformational properties of the more ordered sequence.
['Zhang|Wei|W|', 'Zhang|Jiahai|J|', 'MacRaild|Christopher A|CA|', 'Norton|Raymond S|RS|', 'Anders|Robin F|RF|', 'Zhang|Xuecheng|X|http://orcid.org/0000-0003-4430-8907']
D000595:Amino Acid Sequence D000682:Amyloid D000953:Antigens, Protozoan D017124:Conserved Sequence D064267:Intrinsically Disordered Proteins D066329:Protein Aggregates D000072756:Protein Conformation, alpha-Helical D015800:Protozoan Proteins
Aggregation Merozoite surface protein 2 Intrinsically disordered protein Amyloid fibril Flanking disorder