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

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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
Volume388
Issue number5
DOIs
Publication statusPublished - 22 May 2009
Externally publishedYes

Fingerprint

Synucleins
Parkinson Disease
Mutation
Protein S
Proteins
Neurons

Keywords

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

ASJC Scopus subject areas

  • 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

E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein. / Rospigliosi, Carla C.; McClendon, Sebastian; Schmid, Adrian W.; Ramlall, Trudy F.; Barré, Patrick; Lashuel, Hilal A.; Eliezer, David.

In: Journal of Molecular Biology, Vol. 388, No. 5, 22.05.2009, p. 1022-1032.

Research output: Contribution to journalArticle

Rospigliosi, CC, McClendon, S, Schmid, AW, Ramlall, TF, Barré, P, Lashuel, HA & Eliezer, D 2009, 'E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein', Journal of Molecular Biology, vol. 388, no. 5, pp. 1022-1032. https://doi.org/10.1016/j.jmb.2009.03.065
Rospigliosi CC, McClendon S, Schmid AW, Ramlall TF, Barré P, Lashuel HA et al. E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein. Journal of Molecular Biology. 2009 May 22;388(5):1022-1032. https://doi.org/10.1016/j.jmb.2009.03.065
Rospigliosi, Carla C. ; McClendon, Sebastian ; Schmid, Adrian W. ; Ramlall, Trudy F. ; Barré, Patrick ; Lashuel, Hilal A. ; Eliezer, David. / E46K Parkinson's-Linked Mutation Enhances C-Terminal-to-N-Terminal Contacts in α-Synuclein. In: Journal of Molecular Biology. 2009 ; Vol. 388, No. 5. pp. 1022-1032.
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