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|Title:||Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation|
|Other Titles:||Polyalanine expansions drive a shift into alpha-helical clusters without amyloid-fibril formation|
|Citation:||Nature Structural and Molecular Biology, 2015; 22(12):1008-1015|
|Publisher:||Nature Publishing Group|
|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 and Danny M Hatters|
|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.|
|Description:||Published online 16 November 2015|
|Rights:||© 2015 Nature America, Inc. All rights reserved.|
|Appears in Collections:||Paediatrics publications|
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