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.
复制标题
DOI：
10.1021/bi301662w
复制
发表时间：
2013-05-28
期刊：
影响因子：
2.9
通讯作者：
Sharma KK
中科院分区：
文献类型：
--
作者：
Kannan R;Santhoshkumar P;Mooney BP;Sharma KK
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.
登录
查看更多内容
影响因子：
4.4
作者：
Grey AC;Schey KL
通讯作者：
Schey KL
影响因子：
3.4
作者：
Hariharapura R;Santhoshkumar P;Krishna Sharma K
通讯作者：
Krishna Sharma K
DOI：
10.1073/pnas.1010373107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Ahn, Hyung Jin;Zamolodchikov, Daria;Strickland, Sidney
通讯作者：
Strickland, Sidney
DOI：
10.1073/pnas.0911281106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Hu, Xiaoyan;Crick, Scott L.;Lee, Jin-Moo
通讯作者：
Lee, Jin-Moo
DOI：
10.1073/pnas.82.12.4245
发表时间：
1985-01-01
影响因子：
11.1
作者：
MASTERS, CL;SIMMS, G;BEYREUTHER, K
通讯作者：
BEYREUTHER, K