European Biophysics Journal

, Volume 48, Issue 1, pp 99–110 | Cite as

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 ZhangEmail author
Original Article


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.


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



N-terminal 30 residues of 3D7-MSP2


N-terminal 33 residues of 3D7-MSP2


N-terminal 37 residues of 3D7-MSP2


Circular dichroism


Eukaryote linear motif


N-terminal 30 residues of FC27-MSP2




Intrinsically disordered proteins/regions


Molecular recognition feature


Merozoite surface protein 2


N-terminal 25 residues of MSP2


Nuclear magnetic resonance


Preformed structured element


Short linear motif


Transmission electron microscopy


Thioflavin T





We thank F. Delaglio and A. Bax for providing NMRPipe and NMRDraw, T. D. Goddard and D. Kneller for Sparky. This work was supported by the National Natural Science Foundation of China (Grant Number 31470775), the Australia China Young Scientist Exchange Program (2015), the International Science and Technology Cooperation Plan of Anhui Province (Grant Number 1503062010), and the Key Research Program of the Education Department of Anhui Province (Grant Number KJ2014ZD01). R.S.N. acknowledges fellowship support from the Australian National Health and Medical Research Council.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© European Biophysical Societies' Association 2018

Authors and Affiliations

  1. 1.School of Life SciencesAnhui UniversityHefeiChina
  2. 2.Anhui Provincial Engineering Technology Research Center of Microorganisms and BiocatalysisHefeiChina
  3. 3.Anhui Key Laboratory of Modern BiomanufacturingHefeiChina
  4. 4.School of Life SciencesUniversity of Science and Technology of ChinaHefeiChina
  5. 5.Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia
  6. 6.La Trobe Institute for Molecular ScienceLa Trobe UniversityBundooraAustralia

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