The structural biology of crystallin aggregation: challenges and outlook

Abstract

Crystallin aggregation is characterized by light scattering of large molecular aggregates due to their phase separation in the lens. Low-resolution biophysical studies using multiple techniques have characterized the folding, stability, binding, and aggregation of crystallins in the past but with limited access to their structure, dynamics, and interactions. In this Viewpoint, three schools of experimental structural biology, that is, X-ray crystallography, solution and solid-state NMR spectroscopy, and cryo-electron microscopy, combine to provide atomic resolution details of native crystallins, soluble oligomers, and insoluble amyloid fibrils and amorphous aggregates. Computational structural biology provides additional details on crystallin dynamics and the crucial intercrystallin interactions in these events. Our current understanding of the diverse structural biology of crystallins is consistent with multiple pathways of protein aggregation for different structural intermediates. This Viewpoint combines our efforts with those of others to elucidate the recent progress in these high-resolution studies and proposes an integrated structural biology approach to resolve the complex lens interactome. Overall, I discuss the outstanding questions and evaluate the experimental and theoretical caveats in the field.