Mechanism of a hereditary cataract phenotype. Mutations in alphaA-crystallin activate substrate binding

The Journal of Biological Chemistry
Hanane A Koteiche, Hassane S McHaourab

Abstract

We present a novel hypothesis for the molecular mechanism of autosomal dominant cataract linked to two mutations in the alphaA-crystallin gene of the ocular lens. AlphaA-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 the alphaA-crystallin mutants is predicted to shift the substrate folding equilib...Continue Reading

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Citations

Jun 8, 2012·Biochemistry·Hassane S McHaourabBenjamin W Spiller
Mar 18, 2008·Journal of Biochemistry·Ashis BiswasRam H Nagaraj
Nov 15, 2012·Investigative Ophthalmology & Visual Science·Niklaus H MuellerJ Mark Petrash
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Apr 24, 2007·FEBS Letters·Hassane S McHaourabHanane A Koteiche
Dec 15, 2006·Progress in Retinal and Eye Research·Usha P Andley
Aug 25, 2006·The Biochemical Journal·Heath EcroydJohn A Carver
Mar 8, 2019·Nature Communications·T Reid AldersonAndrew J Baldwin
May 26, 2009·Biochimica Et Biophysica Acta·K Krishna Sharma, Puttur Santhoshkumar

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