Ibuprofen Protects Alpha-Crystallin against Posttranslational Modification by Preventing Protein Cross-Linking

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Abstract
Posttranslational modification of bovine α-crystallin by D-erythrose-4-phosphate, fructose-6-phosphate, .D-ribose-5-phosphate and carbamylation using potassium cyanate induced the loss of chaperone-like activity, as assessed by γ-crystallin aggregation. The presence of high-molecular-weight aggregates indicated that erythrosylated, fructosylated and carbamylated α-crystallins were modified by non-reducible cross-linking. In contrast, ribosylation of α-crystallin induced the formation of reducible cross-links. Analysis of ribosylated, erythrosylated and carbamylated α-crystallin using non-denaturing acrylamide gels showed that the cross-linking did not sterically inhibit the normal aggregate formation or alter the oligomerisation of the aggregate. Co-incubation of ibuprofen in the presence of α-crystallin and the modifying agents protected the chaperone-like activity of α-crystallin, enabling the inhibition of γ-crystallin aggregation. In addition, ibuprofen inhibited the formation of both reducible and non-reducible cross-linked high-molecular-weight α-crystallin aggregates. We show in this paper that ibuprofen can inhibit in vitro cross-linking events responsible for the loss of chaperone-like activity of α-crystallin and suggest that the protective effect of ibuprofen may be exerted by the binding of ibuprofen breakdown products to α-crystallin lysine groups, preventing posttranslational modification responsible for the loss of chaperone-like activity.

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