Skip navigation
Skip navigation

Binding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation

Shammas, Sarah L.; Waudby, Christopher A.; Wang, Shuyu; Buell, Alexander K.; Knowles, Tuomas P.J.; Ecroyd, Heath; Welland, Mark E.; Carver, John A.; Dobson, Christopher M.; Meehan, Sarah

Description

The molecular chaperone αB-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with Aβ amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with Aβ fibrils in vitro. We find that αB-crystallin binds to wild-type Aβ(42) fibrils with micromolar affinity, and also binds to fibrils...[Show more]

dc.contributor.authorShammas, Sarah L.
dc.contributor.authorWaudby, Christopher A.
dc.contributor.authorWang, Shuyu
dc.contributor.authorBuell, Alexander K.
dc.contributor.authorKnowles, Tuomas P.J.
dc.contributor.authorEcroyd, Heath
dc.contributor.authorWelland, Mark E.
dc.contributor.authorCarver, John A.
dc.contributor.authorDobson, Christopher M.
dc.contributor.authorMeehan, Sarah
dc.date.accessioned2016-03-28T23:52:22Z
dc.date.available2016-03-28T23:52:22Z
dc.identifier.issn0006-3495
dc.identifier.urihttp://hdl.handle.net/1885/100890
dc.description.abstractThe molecular chaperone αB-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with Aβ amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with Aβ fibrils in vitro. We find that αB-crystallin binds to wild-type Aβ(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of Aβ(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of αB-crystallin on the seeded growth of Aβ fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of αB-crystallin to seed fibrils strongly inhibits their elongation. Because the lag phase in sigmoidal fibril assembly kinetics is dominated by elongation and fragmentation rates, the chaperone mechanism identified here represents a highly effective means to inhibit fibril proliferation. Together with previous observations of αB-crystallin interaction with α-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation.
dc.description.sponsorshipThis study was supported by the Engineering and Physical Sciences Research Council, UK (S.S. and A.K.B.); Unilever and the Biotechnology and Biological Sciences Research Council (C.A.W.); the Wellcome and Leverhulme Trusts (C.M.D.); the Australian Research Council (J.A.C.); the Australian National Health and Medical Research Council; a Peter Doherty Fellowship (H.E.); a Herchel Smith Harvard Postgraduate Scholarship (S.W.); a Royal Society Dorothy Hodgkin Fellowship (S.M.); and a Bye Fellowship, Magdalene College, Cambridge (A.K.B.).
dc.publisherBiophysical Society
dc.rights© 2011 Biophysical Society. Open access under CC BY-NC-ND license.
dc.sourceBiophysical Journal
dc.subjectamyloid beta-peptides
dc.subjectmolecular imaging
dc.subjectpeptide fragments
dc.subjectprotein binding
dc.subjectprotein structure, secondary
dc.subjectalpha-crystallin b chain
dc.subjectprotein multimerization
dc.titleBinding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume101
dc.date.issued2011
local.identifier.absfor030406
local.identifier.ariespublicationU4217927xPUB797
local.publisher.urlhttp://www.biophysics.org/
local.type.statusPublished Version
local.contributor.affiliationShammas, Sarah L., University of Cambridge, United Kingdom
local.contributor.affiliationWaudby, Christopher A., University Chemical Laboratory, United Kingdom
local.contributor.affiliationWang, Shuyu, University of Cambridge, United Kingdom
local.contributor.affiliationBuell, Alexander K., University of Cambridge, United Kingdom
local.contributor.affiliationKnowles, Tuomas P. J., University of Cambridge, United Kingdom
local.contributor.affiliationEcroyd, Heath, University of Wollongong, Australia
local.contributor.affiliationWelland, Mark E., University of Cambridge, United Kingdom
local.contributor.affiliationCarver, John, College of Physical and Mathematical Sciences, CPMS Research School of Chemistry, RSC General, The Australian National University
local.contributor.affiliationDobson, Christopher M., University of Cambridge, United Kingdom
local.contributor.affiliationMeehan, Sarah, University of Cambridge, United Kingdom
local.identifier.essn1542-0086
local.bibliographicCitation.issue7
local.bibliographicCitation.startpage1681
local.bibliographicCitation.lastpage1689
local.identifier.doi10.1016/j.bpj.2011.07.056
local.identifier.absseo970103
dc.date.updated2016-06-14T08:59:45Z
local.identifier.scopusID2-s2.0-80053379382
local.identifier.thomsonID000295661300014
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

Download

File Description SizeFormat Image
01_Shammas_Binding_of_the_Molecular_2011.pdf902.9 kBAdobe PDFThumbnail


Items in Open Research are protected by copyright, with all rights reserved, unless otherwise indicated.

Updated:  19 May 2020/ Responsible Officer:  University Librarian/ Page Contact:  Library Systems & Web Coordinator