Phosphorylation of the aggregate-forming protein alpha-synuclein on serine-129 inhibits its DNA-bending properties

Sydney E. Dent, Dennisha P. King, Valerie R. Osterberg, Eleanor K. Adams, Marilyn R. Mackiewicz, Tamily A. Weissman, Vivek K. Unni

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Alpha-synuclein (aSyn) is a vertebrate protein, normally found within the presynaptic nerve terminal and nucleus, which is known to form somatic and neuritic aggregates in certain neurodegenerative diseases. Disease-associated aggregates of aSyn are heavily phosphorylated at serine-129 (pSyn), while normal aSyn protein is not. Within the nucleus, aSyn can directly bind DNA, but the mechanism of binding and the potential modulatory roles of phosphorylation are poorly understood. Here we demonstrate using a combination of electrophoretic mobility shift assay and atomic force microscopy approaches that both aSyn and pSyn can bind DNA within the major groove, in a DNA length-dependent manner and with little specificity for DNA sequence. Our data are consistent with a model in which multiple aSyn molecules bind a single 300 base pair (bp) DNA molecule in such a way that stabilizes the DNA in a bent conformation. We propose that serine-129 phosphorylation decreases the ability of aSyn to both bind and bend DNA, as aSyn binds 304 bp circular DNA forced into a bent shape, but pSyn does not. Two aSyn paralogs, beta- and gamma-synuclein, also interact with DNA differently than aSyn, and do not stabilize similar DNA conformations. Our work suggests that reductions in aSyn’s ability to bind and bend DNA induced by serine-129 phosphorylation may be important for modulating aSyn’s known roles in DNA metabolism, including the regulation of transcription and DNA repair.

Original languageEnglish (US)
Article number101552
JournalJournal of Biological Chemistry
Volume298
Issue number2
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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