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J. Biol. Chem., Vol. 283, Issue 13, 8477-8485, March 28, 2008

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Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation^*

Puttur Santhoshkumar, Padmanabha Udupa, Raju Murugesan, and K. Krishna Sharma¹

From the Departments of Ophthalmology and Biochemistry, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65212

Analysis of aged and cataract lenses shows the presence of increased amounts of crystallin fragments in the high molecular weight aggregates of water-soluble and water-insoluble fractions. However, the significance of accumulation and interaction of low molecular weight crystallin fragments in aging and cataract development is not clearly understood. In this study, 23 low molecular mass (<3.5-kDa) peptides in the urea-soluble fractions of young, aged, and aged cataract human lenses were identified by mass spectroscopy. Two peptides, B-(1–18) (MDIAIHHPWIRRPFFPFH) and βA3/A1-(59–74) (SD(N)AYHIERLMSFRPIC), present in aged and cataract lens but not young lens, and a third peptide, S-(167–178) (SPAVQSFRRIVE) present in all three lens groups were synthesized to study the effects of interaction of these peptides with intact -, β-, and -crystallins and alcohol dehydrogenase, a protein used in aggregation studies. Interaction of B-(1–18) and βA3/A1-(59–74) peptides increased the scattering of light by β- and -crystallin and alcohol dehydrogenase. The ability of -crystallin subunits to function as molecular chaperones was significantly reduced by interaction with B-(1–18) and βA3/A1-(59–74) peptides, whereas S peptide had no effect on chaperone-like activity of -crystallin. The βA3/A1-(59–74 peptide caused a 5.64-fold increase in B-crystallin oligomeric mass and partial precipitation. Replacing hydrophobic residues in B-(1–18) and βA3/A1-(59–74) peptides abolished their ability to induce crystallin aggregation and light scattering. Our study suggests that interaction of crystallin-derived peptides with intact crystallins could be a key event in age-related protein aggregation in lens and cataractogenesis.

Received for publication, July 17, 2007 , and in revised form, January 2, 2008.

^* This work is supported in part by National Institutes of Health Grants EY14795 and EY11981 and an unrestricted grant-in-aid from Research to Prevent Blindness (to the Department of Ophthalmology). 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 Ophthalmology, EC213, One Hospital Dr., University of Missouri, Columbia, MO 65212. Tel.: 573-882-8478; Fax: 573-884-4100; E-mail: Sharmak{at}health.missouri.edu.

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