Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2

Wei Zhang, Jiahai Zhang, Christopher A. MacRaild, Raymond S. Norton, Robin F. Anders, Xuecheng Zhang

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)99-110
Number of pages12
JournalEuropean Biophysics Journal
Volume48
Issue number1
DOIs
Publication statusPublished - 2019

Keywords

  • Aggregation
  • Amyloid fibril
  • Flanking disorder
  • Intrinsically disordered protein
  • Merozoite surface protein 2

Cite this

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title = "Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2",
abstract = "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.",
keywords = "Aggregation, Amyloid fibril, Flanking disorder, Intrinsically disordered protein, Merozoite surface protein 2",
author = "Wei Zhang and Jiahai Zhang and MacRaild, {Christopher A.} and Norton, {Raymond S.} and Anders, {Robin F.} and Xuecheng Zhang",
year = "2019",
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Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2. / Zhang, Wei; Zhang, Jiahai; MacRaild, Christopher A.; Norton, Raymond S.; Anders, Robin F.; Zhang, Xuecheng.

In: European Biophysics Journal, Vol. 48, No. 1, 2019, p. 99-110.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2

AU - Zhang, Wei

AU - Zhang, Jiahai

AU - MacRaild, Christopher A.

AU - Norton, Raymond S.

AU - Anders, Robin F.

AU - Zhang, Xuecheng

PY - 2019

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N2 - 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.

AB - 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.

KW - Aggregation

KW - Amyloid fibril

KW - Flanking disorder

KW - Intrinsically disordered protein

KW - Merozoite surface protein 2

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