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J. Biol. Chem., Vol. 281, Issue 20, 14273-14279, May 19, 2006

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Mechanism of a Hereditary Cataract Phenotype

MUTATIONS IN A-CRYSTALLIN ACTIVATE SUBSTRATE BINDING^*

From the Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232

We present a novel hypothesis for the molecular mechanism of autosomal dominant cataract linked to two mutations in the A-crystallin gene of the ocular lens. A-crystallin is a molecular chaperone that plays a critical role in the suppression of protein aggregation and hence in the long term maintenance of lens optical properties. Using a steady state binding assay in which the chaperone-substrate complex is directly detected, we demonstrate that the mutations result in a substantial increase in the level of binding to non-native states of the model substrate T4 lysozyme. The structural basis of the enhanced binding is investigated through equivalent substitutions in the homologous heat shock protein 27. The mutations shift the oligomeric equilibrium toward a dissociated multimeric form previously shown to be the binding-competent state. In the context of a recent thermodynamic model of chaperone function that proposes the coupling of small heat shock protein activation to the substrate folding equilibrium (Shashidharamurthy, R., Koteiche, H. A., Dong, J., and McHaourab, H. S. (2005) J. Biol. Chem. 280, 5281-5289), the enhanced binding by theA-crystallin mutants is predicted to shift the substrate folding equilibrium toward non-native intermediates, i.e. the mutants promote substrate unfolding. Given the high concentration of A-crystallin in the lens, the molecular basis of pathogenesis implied by our results is a gain of function that leads to the binding of undamaged proteins and subsequent precipitation of the saturated -crystallin complexes in the developing lens of affected individuals.

Received for publication, December 5, 2005 , and in revised form, February 21, 2006.

^* This work was supported by Grants R01-12018 and R01-12683 from the NEI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, Vanderbilt University, 2215 Garland Ave., 741 Light Hall, Nashville, TN 37232. Tel.: 615-322-3307; Fax: 615-322-7236; E-mail: Hassane.mchaourab{at}vanderbilt.edu.

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