Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 382, Issue 3, Pages 812-824Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.07.068
Keywords
chaperone; alpha-crystallins; Cu2+ binding; redox silencing; cytoprotection
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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 alpha-crystallins. However, the role of alpha-crystallins in oxidative stress and in Cu2+-mediated processes is not clearly understood. We demonstrate using fluorescence and isothermal titration calorimetry that alpha-crystallins (alpha A- and alpha B-crystallin and its phosphorylation mimic, 3D alpha B-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 CU binding, indicating selectivity 2+ binding induces structural of the Cu2+-binding site(s) in alpha-crystallins. Cu2+ changes and increase in the hydrodynamic radii of a-crystallins. Cu2+ binding increases the stability of alpha-crystallins towards guanidinium chloride-induced unfolding. Chaperone activity of alpha A-crystallin increases significantly upon Cu2+ binding. alpha-Crystallins rescue amyloid beta peptide, A beta(1-40), from Cu2+ -induced aggregation in vitro. alpha-Crystallins inhibit Cu2+- induced oxidation of ascorbate and, hence, prevent the generation of reactive oxygen species. Interestingly, alpha-synuclein, a Cu2+-binding protein, does not inhibit this oxidation process significantly. We find that the Cu2+- sequestering (or redox-silencing) property of alpha-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 alpha-crystallins in Cu2+ homeostasis and helps in understanding their protective role in neurodegenerative diseases and cataract. (C) 2008 Elsevier Ltd. All rights reserved.
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