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Michelle Yu Sung Hooi, Mark J. Raftery, Roger John Willis Truscott; Racemization of Two Proteins over Our Lifespan: Deamidation of Asparagine 76 in γS Crystallin Is Greater in Cataract than in Normal Lenses across the Age Range. Invest. Ophthalmol. Vis. Sci. 2012;53(7):3554-3561. https://doi.org/10.1167/iovs.11-9085.
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Long-lived proteins are widespread in man, yet little is known about the processes that affect their function over time, or their role in age-related diseases.
Racemization of two proteins from normal and cataract human lenses were compared with age using tryptic digestion and LC/mass spectrometry. Asp 151 in αA crystallin and Asn 76 in γS crystallin were studied.
Age-dependent profiles for the two proteins from normal lenses were different. In neither protein did the modifications increase linearly with age. For αA crystallin, racemization occurred most rapidly during the first 15 years of life, with approximately half of L-Asp 151 converted to D-isoAsp, L-isoAsp, and D-Asp in a ratio of 3:1:0.5. Values then changed little. By contrast, racemization of Asn 76 in γS crystallin was slow until age 15, with isoAsp accounting for only 5%. Values remained relatively constant until age 40 when a linear increase (1%/year) took place. When cataract lenses were compared with age-matched normal lenses, there were marked differences in the time courses of the two crystallins. For αA crystallin, there was no significant difference in Asp 151 racemization between cataract and normal lenses. By contrast, in γS crystallin the degree of conversion of Asn 76 to isoAsp in cataract lenses was approximately double that of normals at every age.
Modification of Asn and Asp over time may contribute to denaturation of proteins in the human lens. An accelerated rate of deamidation/racemization at selected sites in proteins, such as γS crystallin, may contribute to cataract formation.
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