Chemoenzymatic Semisynthesis of Phosphorylated α-Synuclein Enables Identification of a Bidirectional Effect on Fibril Formation

ACS Chem Biol. 2020 Mar 20;15(3):640-645. doi: 10.1021/acschembio.9b01038. Epub 2020 Feb 17.

Abstract

Post-translational modifications (PTMs) impact the pathological aggregation of α-synuclein (αS), a hallmark of Parkinson's disease (PD). Here, we synthesize αS phosphorylated at tyrosine 39 (pY39) through a novel route using in vitro enzymatic phosphorylation of a fragment followed by ligation to form the full-length protein. We can execute this synthesis in combination with unnatural amino acid mutagenesis to include two fluorescent labels for Förster resonance energy transfer (FRET) studies. We determine the effect of pY39 on the aggregation of αS and compare our authentically phosphorylated material to the corresponding glutamate 39 "phosphomimetic." Intriguingly, we find that αS-pY39 can either accelerate or decelerate aggregation, depending on the fraction of phosphorylated protein. The αS-E39 mutant can qualitatively reproduce some, but not all, of these effects. FRET measurements and analysis of existing structures of αS help to provide an explanation for this phenomenon. Our results have important implications for the treatment of PD patients with tyrosine kinase inhibitors and highlight the importance of validating phosphomimetics through studies of authentic PTMs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Fluorescent Dyes / chemistry
  • Intercalating Agents / chemistry
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutation
  • Parkinson Disease / metabolism*
  • Peptide Fragments / chemical synthesis*
  • Phosphorylation / drug effects*
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Single Molecule Imaging
  • Solid-Phase Synthesis Techniques
  • Structure-Activity Relationship
  • alpha-Synuclein / chemical synthesis*

Substances

  • Amyloid
  • Fluorescent Dyes
  • Intercalating Agents
  • Mutant Proteins
  • Peptide Fragments
  • alpha-Synuclein