ConspectusCrystallins are transparent, refractive proteins that contribute to the focusing power of the vertebrate eye lens. These proteins are extremely soluble and resist aggregation for decades, even under crowded conditions. Crystallins have evolved to avoid strong interprotein interactions and have unusual hydration properties. Crystallin aggregation resulting from mutation, damage, or aging can lead to cataract, a disease state characterized by opacity of the lens.Different aggregation mechanisms can occur, following multiple pathways and leading to aggregates with varied morphologies. Studies of variant proteins found in individuals with childhood-onset cataract have provided insight into the molecular factors underlying crystallin stability and solubility. Modulation of exposed hydrophobic surface is critical, as is preventing specific intermolecular interactions that could provide nucleation sites for aggregation. Biophysical measurements and structural biology techniques are beginning to provide a detailed picture of how crystallins crowd into the lens, providing high refractivity while avoiding excessively tight binding that would lead to aggregation.Despite the central biological importance of refractivity, relatively few experimental measurements have been made for lens crystallins. Our work and that of others have shown that hydration is important to the high refractive index of crystallin proteins, as are interactions between pairs of aromatic residues and potentially other specific structural features.This Account describes our efforts to understand both the functional and disease states of vertebrate eye lens crystallins, particularly the γ-crystallins. We use a variety of biophysical techniques, notably NMR spectroscopy, to investigate crystallin stability and solubility. In the first section, we describe efforts to understand the relative stability and aggregation propensity of different γS-crystallin variants. The second section focuses on interactions of these proteins with the holdase chaperone αB-crystallin. The third, fourth, and fifth sections explore different modes of aggregation available to crystallin proteins, and the final section highlights the importance of refractive index and the sometimes conflicting demands of selection for refractivity and solubility.
Bibliographical noteFunding Information:
The Martin laboratory’s work on crystallin proteins is supported by NIH Grants 2R01EY021514 to R.W.M and 1R01EY025328 to R.W.M. and D. J. Tobias. Optical spectroscopy data were collected in the UCI Laser Spectroscopy Laboratories under the management of D. Fishman. K.W.R. was supported by NSF Training Grant DGE-1633631 and DMS-1361425 to R.W.M. and C. T. Butts. R.W.M. is a CIFAR Fellow.
The Martin laboratory?s work on crystallin proteins is supported by NIH Grants 2R01EY021514 to R.W.M and 1R01EY025328 to R.W.M. and D. J. Tobias. Optical spectroscopy data were collected in the UCI Laser Spectroscopy Laboratories under the management of D. Fishman. K.W.R. was supported by NSF Training Grant DGE-1633631 and DMS-1361425 to R.W.M. and C. T. Butts. R.W.M. is a CIFAR Fellow.
Copyright © 2020 American Chemical Society.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.