Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation

Saskia Polling, Angelique R. Ormsby, Rebecca J. Wood, Kristie Lee, Cheryl Shoubridge, James N. Hughes, Paul Thomas, Michael D.W. Griffin, Andrew F. Hill, Quill Bowden, Till Böcking, Danny M. Hatters

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Polyglutamine (polyGln) expansions in nine human proteins result in neurological diseases and induce the proteins' tendency to form β-rich amyloid fibrils and intracellular deposits. Less well known are at least nine other human diseases caused by polyalanine (polyAla)-expansion mutations in different proteins. The mechanisms of how polyAla aggregates under physiological conditions remain unclear and controversial. We show here that aggregation of polyAla is mechanistically dissimilar to that of polyGln and hence does not exhibit amyloid kinetics. PolyAla assembled spontaneously into α-helical clusters with diverse oligomeric states. Such clustering was pervasive in cells irrespective of visible aggregate formation, and it disrupted the normal physiological oligomeric state of two human proteins natively containing polyAla: ARX and SOX3. This self-assembly pattern indicates that polyAla expansions chronically disrupt protein behavior by imposing a deranged oligomeric status.

Original languageEnglish
Pages (from-to)1008-1015
Number of pages8
JournalNature Structural and Molecular Biology
Volume22
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Polling, S., Ormsby, A. R., Wood, R. J., Lee, K., Shoubridge, C., Hughes, J. N., ... Hatters, D. M. (2015). Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation. Nature Structural and Molecular Biology, 22(12), 1008-1015. https://doi.org/10.1038/nsmb.3127