E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein

Carla C. Rospigliosi, Sebastian McClendon, Adrian W. Schmid, Trudy F. Ramlall, Patrick Barré, Hilal A. Lashuel, David Eliezer

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Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein α-synuclein (αS) in neurons. Intramolecular contacts between the acidic C-terminal tail of αS and its N-terminal region have been proposed to regulate αS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked αS mutation E46K, which also accelerates the aggregation of the protein, does not interfere with C-terminal-to-N-terminal contacts and instead enhances such contacts. Furthermore, we do not observe a substantial reduction in such contacts in the two previously characterized mutants. Our results suggest that C-terminal-to-N-terminal contacts in αS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate αS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T).

Original languageEnglish
Pages (from-to)1022-1032
Number of pages11
JournalJournal of Molecular Biology
Issue number5
Publication statusPublished - 22 May 2009



  • E46K
  • Parkinson's
  • amyloid
  • protein aggregation
  • synuclein

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Rospigliosi, C. C., McClendon, S., Schmid, A. W., Ramlall, T. F., Barré, P., Lashuel, H. A., & Eliezer, D. (2009). E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein. Journal of Molecular Biology, 388(5), 1022-1032. https://doi.org/10.1016/j.jmb.2009.03.065