Human Lens High-Molecular-Weight α-Crystallin Aggregates

Liang, Jinghang; Akhtar, Nila J.

doi:10.1006/bbrc.2000.3306

Cited by 19 publications

(9 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding correlates well with earlier studies which demonstrated that HMW aggregates in aged and cataract lenses result from exposure of buried β-pleated sheets and increased hydrophobic interactions. 49,50 In both intrinsic tryptophan fluorescence measurement and Bis-ANS binding experiments, we did not see any shift in the emission maximum. tryptophan fluorescence quenching with no shift in emission maximum under the conditions of aggregation has been reported earlier.…”

Section: Discussionmentioning

confidence: 73%

The αA66–80 Peptide Interacts with Soluble α-Crystallin and Induces Its Aggregation and Precipitation: A Contribution to Age-Related Cataract Formation

et al. 2013

View full text Add to dashboard Cite

Formation of protein aggregates in the aging eye lens has been shown to correlate with progressive accumulation of specific low molecular weight (LMW) peptides derived from crystallins. Prominent among the LMW fragments is αA66-80, a peptide derived from αA-crystallin and present in increased concentrations in the water-insoluble (WIS) nuclear fractions of the aging lens. The αA66-80 peptide has amyloid-like properties and preferentially insolubilizes α-crystallin from soluble lens fractions. However, the specific interactions and mechanisms by which the peptide induces α-crystallin aggregation have not been delineated. To gain insights into the mechanisms of peptide-induced aggregation, we investigated the peptide interactions with α-crystallin by various biochemical approaches. The peptide diminishes α-crystallin chaperone ability and drastically promotes α-crystallin aggregation by formation of insoluble peptide-protein complexes through transient intermediates. Bis-ANS studies suggest that the peptide induces changes in hydrophobicity of α-crystallin that could trigger the formation and growth of aggregates. The peptide-α-crystallin aggregates were found to be resistant to dissociation by high ionic strength, whereas guanidium hydrochloride and urea were effective dissociating agents. We conclude that the αA66-80 peptide forms a hydrophobically driven, stable complex with α-crystallin and reduces its solubility. Using isotope-labeled chemical crosslinking and mass spectrometry, we show that the peptide binds to multiple sites, including the chaperone site, C-terminal extension and subunit interaction sites in αB-crystallin, which may explain the anti-chaperone property of the peptide and the consequential age-related accumulation of aggregated proteins. Thus, the α-crystallin-derived peptide could play a role in the pathogenesis of cataract formation in the aging lens.

show abstract

Section: Discussionmentioning

confidence: 73%

The αA66–80 Peptide Interacts with Soluble α-Crystallin and Induces Its Aggregation and Precipitation: A Contribution to Age-Related Cataract Formation

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Two particular properties should be noted as they increase the complexity of the sHSP world: i) the relationships between structural organization, holdase activity and changes in response to modifications of the cellular environment are not well conserved between the different members of the family (Ahmad et al 2008; Aquilina et al 2004; Horwitz et al 2004; Koteiche and McHaourab 2003; Liang and Akhtar 2000; Paul et al 2010; Rogalla et al 1999). ii) sHSP can form mosaic oligomeric structures with the other members of the family.…”

Section: Introductionmentioning

confidence: 99%

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

2012

View full text Add to dashboard Cite

Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participates in many of the traits that permit the malignant phenotype. Thus cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at: (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1 / HSP in malignant transformation and, (3) discovering approaches to therapy based on disrupting the influence of the HSF1 controlled transcriptome in cancer.

show abstract

“…In aged lenses, the appearance of high-molecular mass aggregates (more than 1000 kDa) and insoluble proteins has been observed (7,8).…”

mentioning

confidence: 99%

Protective Effects of l- and d-Carnosine on α-Crystallin Amyloid Fibril Formation: Implications for Cataract Disease

et al. 2009

View full text Add to dashboard Cite

Mildly denaturing conditions induce bovine alpha-crystallin, the major structural lens protein, to self-assemble into fibrillar structures in vitro. The natural dipeptide l-carnosine has been shown to have potential protective and therapeutic significance in many diseases. Carnosine derivatives have been proposed as potent agents for ophthalmic therapies of senile cataracts and diabetic ocular complications. Here we report the inhibitory effect induced by the peptide (l- and d-enantiomeric form) on alpha-crystallin fibrillation and the almost complete restoration of the chaperone activity lost after denaturant and/or heat stress. Scanning force microscopy (SFM), thioflavin T, and a turbidimetry assay have been used to determine the morphology of alpha-crystallin aggregates in the presence and absence of carnosine. DSC and a near-UV CD assay evidenced that the structural precursors of amyloid fibrils are polypeptide chain segments that lack stable structural elements. Moreover, we have found a disassembling effect of carnosine on alpha-crystallin amyloid fibrils. Finally, we show the ability of carnosine to restore most of the lens transparency in organ-cultured rat lenses exposed to similar denaturing conditions that were used for the in vitro experiments.

show abstract

Human Lens High-Molecular-Weight α-Crystallin Aggregates

Cited by 19 publications

References 30 publications

The αA66–80 Peptide Interacts with Soluble α-Crystallin and Induces Its Aggregation and Precipitation: A Contribution to Age-Related Cataract Formation

The αA66–80 Peptide Interacts with Soluble α-Crystallin and Induces Its Aggregation and Precipitation: A Contribution to Age-Related Cataract Formation

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

Protective Effects of l- and d-Carnosine on α-Crystallin Amyloid Fibril Formation: Implications for Cataract Disease

Contact Info

Product

Resources

About