Similarity of the non-amyloid-β component and C-terminal tail of monomeric and tetrameric alpha-synuclein with 14-3-3 sigma

Sarah R. Evans, Colista West, Judith Klein-Seetharaman

Research output: Contribution to journalArticlepeer-review

Abstract

Alpha-synuclein (αSyn) is often described as a predominantly disordered protein that has a propensity to self-assemble into toxic oligomers that are found in patients with Parkinson's and Alzheimer's diseases. αSyn's chaperone behavior and tetrameric structure are proposed to be protective against toxic oligomerization. In this paper, we extended the previously proposed similarity between αSyn and 14-3-3 proteins to the α-helical tetrameric species of αSyn in detail. 14-3-3 proteins are a family of well-folded proteins with seven human isoforms, and function in signal transduction and as molecular chaperones. We investigated protein homology, using sequence alignment, amyloid, and disorder prediction, as well as three-dimensional visualization and protein-interaction networks. Our results show sequence homology and structural similarity between the aggregation-prone non-amyloid-β component (NAC) residues Val-52 to Gly-111 in αSyn and 14-3-3 sigma residues Leu-12 to Gly-78. We identified an additional region of sequence homology in the C-terminal region of αSyn (residues Ser-129 to Asp-135) and a C-terminal loop of 14-3-3 between helix αH and αI (residues Ser-209 to Asp-215). This data indicates αSyn shares conserved domain architecture with small heat shock proteins. We show predicted regions of high amyloidogenic propensity and intrinsic structural disorder in αSyn coincide with amyloidogenic and disordered predictions for 14-3-3 proteins. The homology in the NAC region aligns with residues involved in dimer- and tetramerization of the non-amyloidogenic 14-3-3 proteins. Because 14-3-3 proteins are generally not prone to misfolding, our results lend further support to the hypothesis that the NAC region is critical to the assembly of αSyn into the non-toxic tetrameric state.

Original languageEnglish (US)
Pages (from-to)5348-5359
Number of pages12
JournalComputational and Structural Biotechnology Journal
Volume19
DOIs
StatePublished - Jan 2021
Externally publishedYes

Keywords

  • 14-3-3 proteins
  • Alpha-synuclein
  • Homology
  • Prediction
  • Protein structure
  • Tetramer

ASJC Scopus subject areas

  • Biotechnology
  • Biophysics
  • Structural Biology
  • Biochemistry
  • Genetics
  • Computer Science Applications

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