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

S Polling; AR Ormsby; RJ Wood; K Lee; C Shoubridge; JN Hughes; PQ Thomas; MDW Griffin; AF Hill; Q Bowden; T Böcking; DM Hatters

Journal article

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

S Polling, AR Ormsby, RJ Wood, K Lee, C Shoubridge, JN Hughes, PQ Thomas, MDW Griffin, AF Hill, Q Bowden, T Böcking, DM Hatters

Nature Structural and Molecular Biology | NATURE PUBLISHING GROUP | Published : 2015

DOI: 10.1038/nsmb.3127

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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 vis..

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University of Melbourne Researchers

Michael Griffin Author

Danny M Hatters Author

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Awarded by Australian Research Council

Funding Acknowledgements

This work was funded by the Australian Research Council (Discovery Project Grant DP120102763 (D.M.H.) and Future Fellowships FT120100039 (D.M.H.), FT100100411 (T.B.) and FT100100560 (A.F.H.)) and by the Australian National Health and Medical Research Council (Project Grants APP1049458 (D.M.H.), 628946 (A.F.H.), 465401 (P.Q.T.) and APP1049459 (D.M.H. and T.B.)). The GFP-NLS vector was kindly provided by G. Mosely (University of Melbourne).