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 Q Thomas; Michael D W Griffin; Andrew F Hill; Quill Bowden; Till Böcking; Danny M Hatters

doi:10.1038/nsmb.3127

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

Nat Struct Mol Biol. 2015 Dec;22(12):1008-15. doi: 10.1038/nsmb.3127. Epub 2015 Nov 16.

Authors

Saskia Polling^{1

2}, Angelique R Ormsby^{1

2}, Rebecca J Wood^{1

2}, Kristie Lee³, Cheryl Shoubridge³, James N Hughes⁴, Paul Q Thomas⁴, Michael D W Griffin^{1

2}, Andrew F Hill⁵, Quill Bowden⁶, Till Böcking^{6

7}, Danny M Hatters^{1

2

7}

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.
² Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
³ Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
⁴ School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
⁵ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
⁶ Single Molecule Science and Department of Anatomy, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
⁷ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Australia.

PMID: 26571108
DOI: 10.1038/nsmb.3127

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid / metabolism*
Humans
Peptides / chemistry*
Peptides / metabolism*
Protein Aggregation, Pathological*
Protein Multimerization*
Protein Structure, Secondary

Substances

Amyloid
Peptides
polyalanine