Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction

Ilaria Pelassa, Davide Corà, Federico Cesano, Francisco J. Monje, Pier Giorgio Montarolo, Ferdinando Fiumara

Research output: Contribution to journalArticle

Abstract

The expansion ofhomopolymeric glutamine (polyQ) or alanine (polyA) repeats in certain proteins owing to genetic mutations induces protein aggregation and toxicity, causing at least 18 human diseases. PolyQ and polyA repeats can also associate in the same proteins, but the general extent of their association in proteomes is unknown. Furthermore, the structural mechanisms by which their expansion causes disease are not well understood, and these repeats are generally thought to misfold upon expansion into aggregation-prone b-sheet structures like amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) structures in triggering aggregation and toxicity of polyQ-expanded proteins, raising the possibility that polyA repeats may as wellform these structures,bythemselvesor inassociation with polyQ.Wefound through bioinformatics screenings that polyA, polyQ and polyQA repeats have a phylogenetically graded association in human and nonhuman proteomes and associate/overlap with CC domains. Circular dichroism and cross-linking experiments revealed that polyA repeats can form-alone or with polyQ and polyQA-CC structures that increase in stability with polyA length, forming higher-order multimers and polymers in vitro. Using structure-guided mutagenesis, we studied the relevance of polyA CCs to the in vivo aggregation and toxicity of RUNX2-a polyQ/polyA protein associated with cleidocranial dysplasia upon polyA expansion-and found that the stability of its polyQ/polyA CC controls its aggregation, localization and toxicity. These findings indicate that, like polyQ, polyA repeats formCCstructures that can trigger protein aggregation and toxicity upon expansion inhumangenetic diseases.

Original languageEnglish
Article numberddu049
Pages (from-to)3402-3420
Number of pages19
JournalHuman Molecular Genetics
Volume23
Issue number13
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

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