It is not widely known that there are a number of proteins in the body that are long-lived and some that exist for our lifetime. The list includes spectrin, elastin, collagen, crystallins and components of the nuclear pore complex. Over time, these old proteins become modified, however our knowledge of the molecular details, and which are of most importance, is poorly understood.
We have been characterizing some of these modifications using the human lens as a model system and characterising the reactions using synthetic peptides. Major modifications result from the intrinsic instability of some amino acid residues: serine, asparagine and aspartic acid. Quantitatively the most important reactions are racemisation, deamidation and spontaneous peptide bond cleavage. Unstructured regions of proteins are particularly susceptible to these posttranslational modifications. In the lens, the extent of these reactions increases over time and it is probable that they lead to protein denaturation. The ultimate result is that the lens becomes opaque and that age-related cataract develops. It is likely that the gradual deterioration of long-lived proteins plays a role in other human age-related diseases.