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The structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity

Hochberg, Georg K. A.; Ecroyd, Heath; Liu, Cong; Cox, Dezerae; Cascio, Duilio; Sawaya, Michael R.; Collier, Miranda P.; Stroud, James; Carver, John; Baldwin, Andrew J.; Robinson, Carol V.; Eisenberg, David S.; Benesch, Justin L. P.; Laganowsky, Arthur

Description

Mammalian small heat-shock proteins (sHSPs) are molecular chaperones that form polydisperse and dynamic complexes with target proteins, serving as a first line of defense in preventing their aggregation into either amorphous deposits or amyloid fibrils. Their apparently broad target specificity makes sHSPs attractive for investigating ways to tackle disorders of protein aggregation. The two most abundant sHSPs in human tissue are αB-crystallin (ABC) and HSP27; here we present high-resolution...[Show more]

dc.contributor.authorHochberg, Georg K. A.
dc.contributor.authorEcroyd, Heath
dc.contributor.authorLiu, Cong
dc.contributor.authorCox, Dezerae
dc.contributor.authorCascio, Duilio
dc.contributor.authorSawaya, Michael R.
dc.contributor.authorCollier, Miranda P.
dc.contributor.authorStroud, James
dc.contributor.authorCarver, John
dc.contributor.authorBaldwin, Andrew J.
dc.contributor.authorRobinson, Carol V.
dc.contributor.authorEisenberg, David S.
dc.contributor.authorBenesch, Justin L. P.
dc.contributor.authorLaganowsky, Arthur
dc.date.accessioned2015-12-10T23:08:00Z
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/63105
dc.description.abstractMammalian small heat-shock proteins (sHSPs) are molecular chaperones that form polydisperse and dynamic complexes with target proteins, serving as a first line of defense in preventing their aggregation into either amorphous deposits or amyloid fibrils. Their apparently broad target specificity makes sHSPs attractive for investigating ways to tackle disorders of protein aggregation. The two most abundant sHSPs in human tissue are αB-crystallin (ABC) and HSP27; here we present high-resolution structures of their core domains (cABC, cHSP27), each in complex with a segment of their respective C-terminal regions. We find that both truncated proteins dimerize, and although this interface is labile in the case of cABC, in cHSP27 the dimer can be cross-linked by an intermonomer disulfide linkage. Using cHSP27 as a template, we have designed an equivalently locked cABC to enable us to investigate the functional role played by oligomerization, disordered N and C termini, subunit exchange, and variable dimer interfaces in ABC. We have assayed the ability of the different forms of ABC to prevent protein aggregation in vitro. Remarkably, we find that cABC has chaperone activity comparable to that of the full-length protein, even when monomer dissociation is restricted through disulfide linkage. Furthermore, cABC is a potent inhibitor of amyloid fibril formation and, by slowing the rate of its aggregation, effectively reduces the toxicity of amyloid-β peptide to cells. Overall we present a small chaperone unit together with its atomic coordinates that potentially enables the rational design of more effective chaperones and amyloid inhibitors.
dc.publisherNational Academy of Sciences (USA)
dc.rightsAuthor/s retain copyright
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.titleThe structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume111
dc.date.issued2014
local.identifier.absfor030406 - Proteins and Peptides
local.identifier.ariespublicationu4005981xPUB770
local.type.statusPublished Version
local.contributor.affiliationHochberg, Georg K. A., University of Oxford
local.contributor.affiliationEcroyd, Heath, University of Wollongong
local.contributor.affiliationLiu, Cong, University of California
local.contributor.affiliationCox, Dezerae, University of Wollongong
local.contributor.affiliationCascio, Duilio, University of California
local.contributor.affiliationSawaya, Michael R., University of California
local.contributor.affiliationCollier, Miranda P., University of Oxford
local.contributor.affiliationStroud, James, University of California
local.contributor.affiliationCarver, John, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationBaldwin, Andrew J., University of Oxford
local.contributor.affiliationRobinson, Carol V., Oxford University
local.contributor.affiliationEisenberg, David S., University of California
local.contributor.affiliationBenesch, Justin L. P., Oxford University
local.contributor.affiliationLaganowsky, Arthur, University of Oxford
local.bibliographicCitation.issue16
local.bibliographicCitation.startpageE1562
local.bibliographicCitation.lastpageE1570
local.identifier.doi10.1073/pnas.1322673111
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2015-12-10T09:03:41Z
local.identifier.scopusID2-s2.0-84899118154
local.identifier.thomsonID000334694000005
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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