Isomerization as the secret Achilles' heel of long-lived proteins.

Crystallin proteins, the dominant constituents of the eye lens, are prototypes of long-lived proteins. Such proteins can accumulate harmful modifications over their life span that render them prone to aggregation, which, in the case of lens crystallin, contributes to cataract formation. Lyon et al. now explore the structural and functional consequences of amino acid isomerization in α-crystallins using mass spectrometry, molecular dynamics simulations, and other strategies. Their results highlight the potential deleterious effects of these under-detected modifications on protein structural integrity and function.