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Enhanced degradation and decreased stability of eye lens \alpha-crystallin upon methylglyoxal modification

Kumar, Satish M and Mrudula, T and Mitra, N and Reddy, Bhanuprakash G (2004) Enhanced degradation and decreased stability of eye lens \alpha-crystallin upon methylglyoxal modification. In: Experimental Eye Research, 79 (4). pp. 577-583.


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Methylglyoxal (MGO), a potent glycating agent, forms advanced glycationend products (AGEs) with proteins. Several diabetic complications including cataract are thought to be the result of accumulation of these protein-AGEs. alpha-Crystallin, molecular chaperone of the eye lens, plays an important role in maintaining the transparency of the lens by preventing the aggregation/inactivation of several proteins/enzymes in addition to its structural role. Binding of adenosine-5-triphosphate (ATP) to alpha-crystallin has been shown to enhance its chaperone-like function and protection against proteolytic degradation. In the earlier study, we have shown that modification of a-crystallin by MGO caused altered chaperone-like activity along with structural changes, cross-linking, coloration and subsequent in solubilization leading to scattering of light [Biochem. J. 379 (2004)273]. In the present study, we have investigated ATP binding, stability and degradation of MGO-modified alpha-crystallin. Proteolytic digestion with trypsin and chymotrypsin showed that MGO-modified alpha-crystallinis more susceptible to degradation compared to native a-crystallin.Furthermore, ATP was able to protect native alpha-crystallin against proteolytic cleavage but not MGO-modified alpha-crystallin.Interestingly, binding studies indicate decreased ATP binding to MGO-modified alpha-crystallin and support the decreased protection by ATP against proteolysis. In addition, differential scanning calorimetric and denaturant-induced unfolding studies indicate that modification of alpha-crystallin by MGO leads to decreased stability.These results indicate that MGO-modification of alpha-crystallin causes partial unfolding and decreased stability leading to enhanced proteolysis. Cross-linking of these degraded products could result inaggregation and subsequent insolubilization as observed in senile and diabetic cataract lenses.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to Elsevier.
Keywords: a-crystallin;lens;methylglyoxal;trypsin;chymotrypsin;ATP;stability;degradation;differential scanning calorimetry
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Depositing User: B.S Priyanka
Date Deposited: 23 Feb 2005
Last Modified: 19 Sep 2010 04:18
URI: http://eprints.iisc.ac.in/id/eprint/2843

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