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Cataract-associated P23T γ 3D-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH

Boatz, JC and Whitley, MJ and Li, M and Gronenborn, AM and Van Der Wel, PCA (2017) Cataract-associated P23T γ 3D-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH. Nature Communications, 8.

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Abstract

© 2017 The Author(s). Cataracts cause vision loss through the large-scale aggregation of eye lens proteins as a result of ageing or congenital mutations. The development of new treatments is hindered by uncertainty about the nature of the aggregates and their mechanism of formation. We describe the structure and morphology of aggregates formed by the P23T human Î 3D-crystallin mutant associated with congenital cataracts. At physiological pH, the protein forms aggregates that look amorphous and disordered by electron microscopy, reminiscent of the reported formation of amorphous deposits by other crystallin mutants. Surprisingly, solid-state NMR reveals that these amorphous deposits have a high degree of structural homogeneity at the atomic level and that the aggregated protein retains a native-like conformation, with no evidence for large-scale misfolding. Non-physiological destabilizing conditions used in many in vitro aggregation studies are shown to yield qualitatively different, highly misfolded amyloid-like fibrils.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Boatz, JC
Whitley, MJmjw100@pitt.eduMJW1000000-0001-8830-7514
Li, M
Gronenborn, AMamg100@pitt.eduAMG100
Van Der Wel, PCApvdwel@pitt.eduPVDWEL0000-0002-5390-3321
Date: 5 May 2017
Date Type: Publication
Journal or Publication Title: Nature Communications
Volume: 8
DOI or Unique Handle: 10.1038/ncomms15137
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
Date Deposited: 28 Sep 2017 17:42
Last Modified: 22 Mar 2018 22:55
URI: http://d-scholarship.pitt.edu/id/eprint/33219

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