Selective Cu2+ binding, redox silencing, and cytoprotective effects of the small heat shock proteins αA- and αB-crystallin

Ahmad, Md. Faiz ; Singh, Devendra ; Taiyab, Aftab ; Ramakrishna, Tangirala ; Raman, Bakthisaran ; Mohan Rao, Ch. (2008) Selective Cu2+ binding, redox silencing, and cytoprotective effects of the small heat shock proteins αA- and αB-crystallin Journal of Molecular Biology, 382 (3). pp. 812-824. ISSN 0022-2836

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Oxidative stress and Cu2+ have been implicated in several neurodegenerative diseases and in cataract. Oxidative stress, as well as Cu2+, is also known to induce the expression of the small heat shock proteins α-crystallins. However, the role of α-crystallins in oxidative stress and in Cu2+-mediated processes is not clearly understood. We demonstrate using fluorescence and isothermal titration calorimetry that α-crystallins (αA- and αB-crystallin and its phosphorylation mimic, 3DαB-crystallin) bind Cu2+ with close to picomolar range affinity. The presence of other tested divalent cations such as Zn2+, Mg2+, and Ca2+ does not affect Cu2+ binding, indicating selectivity of the Cu2+-binding site(s) in α-crystallins. Cu2+ binding induces structural changes and increase in the hydrodynamic radii of α-crystallins. Cu2+ binding increases the stability of α-crystallins towards guanidinium chloride-induced unfolding. Chaperone activity of αA-crystallin increases significantly upon Cu2+ binding. α-Crystallins rescue amyloid beta peptide, Aβ1–40, from Cu2+-induced aggregation in vitro. α-Crystallins inhibit Cu2+-induced oxidation of ascorbate and, hence, prevent the generation of reactive oxygen species. Interestingly, α-synuclein, a Cu2+-binding protein, does not inhibit this oxidation process significantly. We find that the Cu2+-sequestering (or redox-silencing) property of α-crystallins confers cytoprotection. To the best of our knowledge, this is the first study to reveal high affinity (close to picomolar) for Cu2+ binding and redox silencing of Cu2+ by any heat shock protein. Thus, our study ascribes a novel functional role to α-crystallins in Cu2+ homeostasis and helps in understanding their protective role in neurodegenerative diseases and cataract.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:Chaperone; α-crystallins; Cu2+ Binding; Redox Silencing; Cytoprotection
ID Code:36819
Deposited On:16 Apr 2011 14:28
Last Modified:29 Nov 2011 10:08

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