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The Structure and Stability of the Disulfide-Linked ?S-Crystallin Dimer Provide Insight into Oxidation Products Associated with Lens Cataract Formation

Thorn, David; Grosas, Aidan; Mabbitt, Peter; Ray, Nicholas; Jackson, Colin; Carver, John

Description

The reducing environment in the eye lens diminishes with age, leading to significant oxidative stress. Oxidation of lens crystallin proteins is the major contributor to their destabilization and deleterious aggregation that scatters visible light, obscures vision, and ultimately leads to cataract. However, the molecular basis for oxidation-induced aggregation is unknown. Using X-ray crystallography and small-angle X-ray scattering, we describe the structure of a disulfide-linked dimer of human...[Show more]

dc.contributor.authorThorn, David
dc.contributor.authorGrosas, Aidan
dc.contributor.authorMabbitt, Peter
dc.contributor.authorRay, Nicholas
dc.contributor.authorJackson, Colin
dc.contributor.authorCarver, John
dc.date.accessioned2020-03-26T04:32:46Z
dc.identifier.issn0022-2836
dc.identifier.urihttp://hdl.handle.net/1885/202479
dc.description.abstractThe reducing environment in the eye lens diminishes with age, leading to significant oxidative stress. Oxidation of lens crystallin proteins is the major contributor to their destabilization and deleterious aggregation that scatters visible light, obscures vision, and ultimately leads to cataract. However, the molecular basis for oxidation-induced aggregation is unknown. Using X-ray crystallography and small-angle X-ray scattering, we describe the structure of a disulfide-linked dimer of human γS-crystallin that was obtained via oxidation of C24. The γS-crystallin dimer is stable at glutathione concentrations comparable to those in aged and cataractous lenses. Moreover, dimerization of γS-crystallin significantly increases the protein’s propensity to form large insoluble aggregates owing to non-cooperative domain unfolding, as is observed in crystallin variants associated with early-onset cataract. These findings provide insight into how oxidative modification of crystallins contributes to cataract and imply that early-onset and age-related forms of the disease share comparable development pathways.
dc.description.sponsorshipA.B.G. is supported by an Australian Postgraduate Award. D.C.T. is supported by a grant from the National Health and Medical Research Council of Australia (Grant No. 1068087) awarded to J.A.C.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherElsevier
dc.rights© 2018 Elsevier Ltd
dc.sourceJournal of Molecular Biology
dc.titleThe Structure and Stability of the Disulfide-Linked ?S-Crystallin Dimer Provide Insight into Oxidation Products Associated with Lens Cataract Formation
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume431
dc.date.issued2019
local.identifier.absfor030406 - Proteins and Peptides
local.identifier.ariespublicationu3102795xPUB575
local.publisher.urlhttps://www.elsevier.com/
local.type.statusPublished Version
local.contributor.affiliationThorn, David, College of Science, ANU
local.contributor.affiliationGrosas, Aidan, College of Science, ANU
local.contributor.affiliationMabbitt, Peter, College of Science, ANU
local.contributor.affiliationRay, Nicholas, College of Science, ANU
local.contributor.affiliationJackson, Colin, College of Science, ANU
local.contributor.affiliationCarver, John, College of Science, ANU
local.description.embargo2037-12-31
dc.relationhttp://purl.org/au-research/grants/nhmrc/1068087
local.bibliographicCitation.issue3
local.bibliographicCitation.startpage483
local.bibliographicCitation.lastpage497
local.identifier.doi10.1016/j.jmb.2018.12.005
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2019-11-25T07:44:55Z
local.identifier.scopusID2-s2.0-85059354041
CollectionsANU Research Publications

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