On the interaction of α-crystallin with unfolded proteins

Carver, John A.; Guerreiro, Nelson; Nicholls, K. A.; Truscott, Roger J.W.

doi:10.1016/0167-4838(95)00146-l

Cited by 103 publications

(102 citation statements)

References 25 publications

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“…From the analytical ultracentrifugation data (Figs. 2, 5, 7, and 8), there is no evidence of an interaction between monomeric apoC-II and ␣-crystallin, consistent with previous observations that ␣-crystallin does not bind to unfolded proteins (35).…”

Section: Discussionsupporting

confidence: 77%

“…Reduced ␣-lactalbumin adopts a molten globulelike state that is prone to aggregation (35). Stoichiometric concentrations of ␣-crystallin are required to significantly suppress this aggregation (23,35), whereas a similar stoichiometry is observed for the stabilization of other stressed proteins (16,17,(31)(32)(33). From a variety of studies, it has been concluded that ␣-crystallin interacts specifically with partly folded intermediates that deviate from the protein folding pathway along the off-folding pathway toward an aggregated and precipitating species (23,31).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas hydrophobic interactions are involved in the chaperone action of ␣-crystallin, the specific mechanism of this interaction is not known (33)(34)(35). ␣-Crystallin does not bind to unfolded proteins or compact folded proteins (35) or to chemically modified, molten-globule states that are stable in solution and do not aggregate (31,36). Reduced ␣-lactalbumin adopts a molten globulelike state that is prone to aggregation (35).…”

Section: Discussionmentioning

confidence: 99%

“…␣-Crystallin does not bind to unfolded proteins or compact folded proteins (35) or to chemically modified, molten-globule states that are stable in solution and do not aggregate (31,36). Reduced ␣-lactalbumin adopts a molten globulelike state that is prone to aggregation (35). Stoichiometric concentrations of ␣-crystallin are required to significantly suppress this aggregation (23,35), whereas a similar stoichiometry is observed for the stabilization of other stressed proteins (16,17,(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

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The Molecular Chaperone, α-Crystallin, Inhibits Amyloid Formation by Apolipoprotein C-II

Hatters

Lindner

Carver

et al. 2001

Journal of Biological Chemistry

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Under lipid-free conditions, human apolipoprotein C-II (apoC-II) exists in an unfolded conformation that over several days forms amyloid ribbons. We examined the influence of the molecular chaperone, ␣-crystallin, on amyloid formation by apoC-II. Time-dependent changes in apoC-II turbidity (at 0.3 mg/ml) were suppressed potently by substoichiometric subunit concentrations of ␣-crystallin (1-10 g/ml). ␣-Crystallin also inhibits time-dependent changes in the CD spectra, thioflavin T binding, and sedimentation coefficient of apoC-II. This contrasts with stoichiometric concentrations of ␣-crystallin required to suppress the amorphous aggregation of stressed proteins such as reduced ␣-lactalbumin. Two pieces of evidence suggest that ␣-crystallin directly interacts with amyloidogenic intermediates. First, sedimentation equilibrium and velocity experiments exclude high affinity interactions between ␣-crystallin and unstructured monomeric apoC-II. Second, the addition of ␣-crystallin does not lead to the accumulation of intermediate sized apoC-II species between monomer and large aggregates as indicated by gel filtration and sedimentation velocity experiments, suggesting that ␣-crystallin does not inhibit the relatively rapid fibril elongation upon nucleation. We propose that ␣-crystallin interacts stoichiometrically with partly structured amyloidogenic precursors, inhibiting amyloid formation at nucleation rather than the elongation phase. In doing so, ␣-crystallin forms transient complexes with apoC-II, in contrast to its chaperone behavior with stressed proteins.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Molecular Chaperone, α-Crystallin, Inhibits Amyloid Formation by Apolipoprotein C-II

Hatters

Lindner

Carver

et al. 2001

Journal of Biological Chemistry

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“…bisANS is a polarity-sensitive probe that has been used to monitor changes in exposed hydrophobic regions in sHSPs (23,24). There was a progressive decrease in the fluorescence of bisANS bound to clusterin with temperature over the range 20 -50°C (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Poon¹,

Rybchyn

Easterbrook‐Smith

et al. 2002

Journal of Biological Chemistry

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100

105

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Many features of the chaperone action of clusterin are similar to those of the intracellular small heat shock proteins (sHSPs) that, like clusterin, exist in solution as heterogeneous aggregates. Increased temperature induces dissociation of some sHSP aggregates and an enhanced chaperone action, suggesting that a dissociated form is the active chaperone species. We recently reported that clusterin aggregates dissociate at mildly acidic pH. To further explore the similarities between clusterin and the sHSPs, we tested the effects of temperature and pH on the structure of clusterin and its chaperone action. Our results demonstrate that increased temperature does not induce dissociation of clusterin aggregates, or other major structural changes, and has little effect on its chaperone action. However, we show that the chaperone action of clusterin is enhanced at mildly acidic pH. Clusterin is the first chaperone shown to be activated by reduced pH. This unique mode of activation appears to result from an increase in regions of solvent-exposed hydrophobicity, which is independent of any major changes in secondary or tertiary structure. We propose a model in which low pH-induced dissociation of clusterin aggregates increases the abundance of the heterodimeric chaperone-active species, which has greater hydrophobicity exposed to solution.

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Recognition between flexible protein molecules: induced and assisted folding

Demchenko

2001

J. Mol. Recognit.

159

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On the interaction of α-crystallin with unfolded proteins

Cited by 103 publications

References 25 publications

The Molecular Chaperone, α-Crystallin, Inhibits Amyloid Formation by Apolipoprotein C-II

The Molecular Chaperone, α-Crystallin, Inhibits Amyloid Formation by Apolipoprotein C-II

Mildly Acidic pH Activates the Extracellular Molecular Chaperone Clusterin

Recognition between flexible protein molecules: induced and assisted folding

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