Serine phosphorylation suppresses huntingtin amyloid accumulation by altering protein aggregation properties

Rakesh Mishra, Cody L Hoop, Ravindra Kodali, Bankanidhi Sahoo, Patrick C A van der Wel, Ronald Wetzel

Research output: Contribution to journalArticleAcademicpeer-review

54 Citations (Scopus)

Abstract

Aggregation of expanded polyglutamine repeat-containing fragments of the huntingtin (htt) protein may play a key role in Huntington's disease. Consistent with this hypothesis, two Ser-to-Asp mutations in the 17-amino-acid N-terminal htt(NT) segment abrogate both visible brain aggregates and disease symptoms in a full-length Q(97) htt mouse model while compromising aggregation kinetics and aggregate morphology in an htt fragment in vitro [Gu et al. (2009). Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron64, 828-840]. The htt(NT) segment has been shown to play a critical role in facilitating nucleation of amyloid formation in htt N-terminal exon1 fragments. We show here how these Ser-to-Asp mutations dramatically affect aggregation kinetics and aggregate structural integrity. First, these negatively charged Ser replacements impair the assembly of the α-helical oligomers that play a critical role in htt amyloid nucleation, thus providing an explanation for reduced amyloid formation rates. Second, these sequence modifications alter aggregate morphology, decrease aggregate stability, and enhance the steric accessibility of the htt(NT) segment within the aggregates. Together, these changes make the sequence-modified peptides kinetically and thermodynamically less likely to aggregate and more susceptible, if they do, to posttranslational modifications and degradation. These effects also show how phosphorylation of a protein might achieve cellular effects via direct impacts on the protein's aggregation properties. In fact, preliminary studies on exon1-like molecules containing phosphoryl-Ser residues at positions 13 and 16 show that they reduce aggregation rates and generate atypical aggregate morphologies similar to the effects of the Ser-to-Asp mutants.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJournal of Molecular Biology
Volume424
Issue number1-2
DOIs
Publication statusPublished - 23-Nov-2012
Externally publishedYes

Keywords

  • Amino Acid Sequence
  • Amyloid/metabolism
  • Animals
  • Exons
  • Humans
  • Huntingtin Protein
  • Kinetics
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins/genetics
  • Phosphorylation
  • Serine/metabolism
  • Thermodynamics

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