Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies

α-synuclein phosphorylation at tyrosine 125

Mirva Hejjaoui, Sara Butterfield, Bruno Fauvet, Filip Vercruysse, Jia Cui, Igor Dikiy, Michel Prudent, Diana Olschewski, Yan Zhang, David Eliezer, Hilal A. Lashuel

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Despite increasing evidence that supports the role of different post-translational modifications (PTMs) in modulating α-synuclein (α-syn) aggregation and toxicity, relatively little is known about the functional consequences of each modification and whether or not these modifications are regulated by each other. This lack of knowledge arises primarily from the current lack of tools and methodologies for the site-specific introduction of PTMs in α-syn. More specifically, the kinases that mediate selective and efficient phosphorylation of C-terminal tyrosine residues of α-syn remain to be identified. Unlike phospho-serine and phospho-threonine residues, which in some cases can be mimicked by serine/threonine-glutamate or aspartate substitutions, there are no natural amino acids that can mimic phospho-tyrosine. To address these challenges, we developed a general and efficient semisynthetic strategy that enables the site-specific introduction of single or multiple PTMs and the preparation of homogeneously C-terminal modified forms of α-syn in milligram quantities. These advances have allowed us to investigate, for the first time, the effects of selective phosphorylation at Y125 on the structure, aggregation, membrane binding, and subcellular localization of α-syn. The development of semisynthetic methods for the site-specific introduction of single or PTMs represents an important advance toward determining the roles of such modifications in α-syn structure, aggregation, and functions in heath and disease.

Original languageEnglish
Pages (from-to)5196-5210
Number of pages15
JournalJournal of the American Chemical Society
Volume134
Issue number11
DOIs
Publication statusPublished - 21 Mar 2012
Externally publishedYes

Fingerprint

Synucleins
Phosphorylation
Post Translational Protein Processing
Tyrosine
Agglomeration
Threonine
Proteins
Serine
Aspartic Acid
Toxicity
Amino acids
Glutamic Acid
Substitution reactions
Phosphotransferases
Membranes
Amino Acids

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies : α-synuclein phosphorylation at tyrosine 125. / Hejjaoui, Mirva; Butterfield, Sara; Fauvet, Bruno; Vercruysse, Filip; Cui, Jia; Dikiy, Igor; Prudent, Michel; Olschewski, Diana; Zhang, Yan; Eliezer, David; Lashuel, Hilal A.

In: Journal of the American Chemical Society, Vol. 134, No. 11, 21.03.2012, p. 5196-5210.

Research output: Contribution to journalArticle

Hejjaoui, M, Butterfield, S, Fauvet, B, Vercruysse, F, Cui, J, Dikiy, I, Prudent, M, Olschewski, D, Zhang, Y, Eliezer, D & Lashuel, HA 2012, 'Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies: α-synuclein phosphorylation at tyrosine 125', Journal of the American Chemical Society, vol. 134, no. 11, pp. 5196-5210. https://doi.org/10.1021/ja210866j
Hejjaoui, Mirva ; Butterfield, Sara ; Fauvet, Bruno ; Vercruysse, Filip ; Cui, Jia ; Dikiy, Igor ; Prudent, Michel ; Olschewski, Diana ; Zhang, Yan ; Eliezer, David ; Lashuel, Hilal A. / Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies : α-synuclein phosphorylation at tyrosine 125. In: Journal of the American Chemical Society. 2012 ; Vol. 134, No. 11. pp. 5196-5210.
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