Interaction of the Molecular Chaperone αB-Crystallin with α-Synuclein: Effects on Amyloid Fibril Formation and Chaperone Activity

Rekas, Agata; Adda, Christopher G.; Aquilina, J. Andrew; Barnham, Kevin J.; Sunde, Margaret; Galatis, Denise; Williamson, Nicholas A.; Masters, Colin L.; Anders, Robin F.; Robinson, Carol V.; Cappai, Roberto; Carver, John A.

doi:10.1016/j.jmb.2004.05.054

Cited by 202 publications

(241 citation statements)

References 69 publications

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“…Also, the chaperone activity of αB-crystallin can be easily compared with well-established data on its chaperone activity against amorphously aggregating target proteins. Thus, studies have shown that αB-crystallin inhibits the fibrillation of α-synuclein [48, 83,93], β2-microglobulin [94] (Esposito, Carver, et al, unpublished results), κ-casein [95,96], the ccβ-Trp peptide [95], apoC-II [97], and the prion protein (Ecroyd, unpublished results). In doing so, αB-crystallin acts as a chaperone under a range of solvent conditions, including at pH values as low as 2.5 against β2-microglobulin fibrillation [94].…”

Section: Shsps and Alzheimer's Diseasementioning

confidence: 99%

“…This is in contrast to its mechanism of action in preventing fibril formation by α-synuclein and κ-casein, whereby αB-crystallin forms a stable, soluble chaperone-target protein complex with the partially folded intermediate of these target proteins (i.e. a 'reservoir of intermediates') [48, 93,95]. This is analogous to the mechanism of chaperone action used by sHsps against amorphously aggregating proteins [2] (Fig.…”

Section: Shsps and The Aβ Peptidesmentioning

confidence: 99%

“…In the case of α-synuclein, αB-crystallin redirects the protein from the amyloid fibril forming pathway to the amorphous aggregation pathway (see Fig. 2) [93], a process that would benefit the cell since these amorphous aggregates are non-toxic and more easily degraded through the ubiquitin-proteasome system. In addition, αB-crystallin is able to halt the increase in ThT fluorescence associated with fibril formation of α-synuclein after it has commenced, but has no capacity to disassemble preformed fibrils [48].…”

Section: Shsps and The Aβ Peptidesmentioning

confidence: 99%

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Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

220

234

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Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alpha B-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials. Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.

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Section: Shsps and Alzheimer's Diseasementioning

confidence: 99%

Section: Shsps and The Aβ Peptidesmentioning

confidence: 99%

Section: Shsps and The Aβ Peptidesmentioning

confidence: 99%

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Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

220

234

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“…It has been shown that synelfin, an ␣-synuclein homolog found in zebra finches, is up-regulated during song-learning, which suggests that the protein is involved in neuronal plasticity [20]. Additionally, ␣-synuclein has been implicated in biochemical pathways involving neuronal cell apoptosis [21], regulation of dopamine [22], and molecular chaperoning [23].…”

mentioning

confidence: 99%

Protein-metal interactions of calmodulin and α-synuclein monitored by selective noncovalent adduct protein probing mass spectrometry

Julian

2008

J. Am. Soc. Mass Spectrom.

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The© metal© binding© properties© of© proteins© are© biologically© significant,© particularly© in© relationship©to©the©molecular©origins©of©disease©and©the©discovery©of©therapeutic©pharmaceutical treatments.© Herein,© we© demonstrate© that© selective© noncovalent© adduct© protein© probing© mass spectrometry©(SNAPP-MS)©is©a©sensitive©technique©to©investigate©the©structural©effects©of protein-metal© interactions.© We© utilize© specific,© noncovalent© interactions© between© 18-crown-6 ether© (18C6)© and© lysine© to© probe© protein© structure© in© the© presence© and© absence© of© metal© ions. Application©of©SNAPP-MS©to©the©calmodulin-Ca 2ϩ© system©demonstrates©that©changes©in protein© structure© are© reflected© in© a© substantial© change© in© the© number© and© intensity© of© 18C6s, which© bind© to© the© protein© as© observed© by© MS.© In© this© manner,© SNAPP© is© demonstrated© to© be a© sensitive© technique© for© monitoring© ligand-induced© conformational© rearrangements© in© proteins.©In©addition,©SNAPP©is©well-suited©to©examine©the©properties©of©natively©unfolded proteins,© where© structural© changes© are© more© difficult© to© detect© by© other© methods.© For© example, ␣-synuclein© is© a© protein© associated© in© the© pathology© of© Parkinson's© disease,© which© is© known© to aggregate© more© rapidly© in© the© presence© of© Al 3ϩ© and© Cu 2ϩ .© The© 18C6© SNAPP© distributions© for ␣-synuclein© change© dramatically© in© the© presence© of© 3© M Al 3ϩ ,© revealing© that© Al 3ϩ© binding causes© a© significant© change© in© the© conformational© dynamics© of© the© monomeric© form© of© this disordered© protein.© In© contrast,© binding© of© Cu 2ϩ© does© not© induce© a© significant© shift© in© 18C6 binding,© suggesting© that© noteworthy© structural© reorganizations© at© the© monomeric© level© are minimal.© These© results© are© consistent© with© the© idea© that© the© metal-induced© aggregation© caused by© Al 3ϩ© and© Cu 2ϩ© proceed© by© independent© pathways

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“…95,96 It was recently found that the chaperone alpha-B-crystallin (a sHsp) inhibits, in vitro, the formation of fibrils by wild-type alpha-synucleins and by the two mutant alpha-synucleins implicated in early-onset Parkinson disease. 97 Inhibition of fibrillization was accompanied by formation of large, irregular, aggregates containing alpha-B-crystallin and alpha-synuclein. These amorphous aggregates would presumably be less stable and more easily disaggregated by specialized chaperones than are the fibrils formed by alpha-synuclein in the absence of alpha-B-crystallin.…”

Section: Alpha-synuclein: An Emerging Chaperone?mentioning

confidence: 99%

Genetic disorders involving molecular-chaperone genes: A perspective

Macario

Grippo

Macario

2005

Genetics in Medicine

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Molecular chaperones are important for maintaining a functional set of proteins in all cellular compartments.Together with protein degradation machineries (e.g., the ubiquitin-proteasome system), chaperones form the core of the cellular protein-quality control mechanism. Chaperones are proteins, and as such, they can be affected by mutations. At least 15 disorders have been identified that are associated with mutations in genes encoding chaperones, or molecules with features suggesting that they function as chaperones. These chaperonopathies and a few other candidates are presented in this article. In most cases, the mechanisms by which the defective genes contribute to the observed phenotypes are still uncharacterized. However, the reported observations definitely

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Interaction of the Molecular Chaperone αB-Crystallin with α-Synuclein: Effects on Amyloid Fibril Formation and Chaperone Activity

Cited by 202 publications

References 69 publications

Crystallin proteins and amyloid fibrils

Crystallin proteins and amyloid fibrils

Protein-metal interactions of calmodulin and α-synuclein monitored by selective noncovalent adduct protein probing mass spectrometry

Genetic disorders involving molecular-chaperone genes: A perspective

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