Crystallins

Crystallins are water-soluble proteins so named for their high abundance in the crystal-line lens. Crystallins can be divided into 2 groups. One group includes α-crystallin and the β,γ-crystallin family, both of which seem to be present in all vertebrate lenses but have also been demonstrated in other ocular tissues. The second group consists of the taxonspecific crystallins, which are present only in certain species.

• Andley UP. Crystallins in the eye: function and pathology. Prog Retin Eye Res. 2007; 26(1):78–98.

• Slingsby C, Wistow GJ. Functions of crystallins in and out of lens: roles in elongated and post-mitotic cells. Prog Biophys Mol Biol. 2014;115(1):52–67.

α-Crystallin α-Crystallin is a member of the small heat shock protein family. Heat shock proteins are molecular chaperones; they stabilize partially folded proteins and prevent them from aggregating. Zinc ions enhance the chaperone function and stability of α-crystallin. Because protein aggregates in the lens scatter light and cause loss of transparency, the antiaggregative function of α-crystallin is crucial to the long-term maintenance of transparency in the fibers of the lens nucleus, where synthesis of new protein is impossible and protein molecules must exist for decades. Mutations in the α-crystallin gene result in premature cataract development; this has been confirmed in knockout models.

• Berry V, Francis P, Ashwin Reddy M, et al. Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans. Am J Hum Genet. 2001;69(5):1141–1145.

• Brady JP, Garland D, Duglas-Tabor Y, Robinson WG Jr, Groome A, Wawrousek EF. Targeted disruption of the mouse αA-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein αB-crystallin. Proc Natl Acad Sci U S A. 1997;94(3):884–889.

β,γ-Crystallins β,γ-Crystallins are divided into 2 groups, β-crystallins and γ-crystallins, on the basis of molecular mass and isoelectric points. β-Crystallins exist as polymers, and γ-crystallins are monomeric. The specific functions of the β,γ-crystallins are unknown. Acquired posttranslational modifications of β-crystallins have been associated with cataract formation. Most expression of γ-crystallins occurs early in development; thus, they tend to be most concentrated in the nuclear region of the lens. Given their compact and symmetric structures (which can pack very densely), γ-crystallins tend to be highly concentrated in aged, hard lenses, which have little to no accommodative ability.

Taxon-specific crystallins In addition to the α-crystallin and β,γ-crystallins found in all vertebrate lenses, other proteins are abundantly expressed in various phylogenetic groups. Taxon-specific crystallins have not been demonstrated in humans. However, they are present in the developing eye of other species. Most taxon-specific crystallins are oxidoreductases, which bind pyridine nucleotides, and their presence in the lens significantly increases the concentration of the bound nucleotides. Reduced nucleotides absorb ultraviolet (UV) light and may protect the retina from UV-induced oxidation.

Cytoskeletal and membrane proteins

Although most proteins in the normal lens are water soluble, several important structural proteins can be solubilized only in the presence of chaotropic agents or detergents. These water-insoluble proteins include the cytoskeletal elements actin (actin filaments), vimentin (intermediate filaments), and tubulin (microtubules), as well as 2 additional proteins called filensin and phakinin. The last 2 proteins have been found only in lens-fiber cells and compose a cytoskeletal structure, the beaded filament, which is unique to the lens. The filamentous structures of the cytoskeleton provide structural support to the cells and play crucial roles in processes such as differentiation, motility and shape change, and organization of the cytoplasm. Mutations of the beaded filament have been shown to result in congenital cataract formation.

Lens-fiber membranes have 1 quantitatively dominant protein, MIP. MIP is expressed only in lens-fiber cells and was earlier thought to be a gap-junction protein. In fact, it is not a connexin but rather an aquaporin—a member of a large, diverse family of proteins involved in regulating water transport. MIP has been reported to function as a water channel and to play a role in cell adhesion. Mutations in the MIP gene lead to cataract formation.

• Chepelinsky AB. Structural function of MIP/aquaporin 0 in the eye lens; genetic defects lead to congenital inherited cataracts. Handb Exp Pharmacol. 2009;(190):265–297.

• Jakobs PM, Hess JF, FitzGerald PG, Kramer P, Weleber RG, Litt M. Autosomal-dominant congenital cataract associated with a deletion mutation in the human beaded filament protein gene BFSP2. Am J Hum Genet. 2000;66(4):1432–1436.

Posttranslational modifications to lens proteins

The proteins of the lens are some of the longest-lived in the body; the oldest ones (in the center of the lens nucleus) are synthesized before birth. As would be expected, these proteins become structurally modified in various ways: oxidation of sulfur and aromatic residue side chains, inter- and intrapolypeptide crosslinking, glycation, racemization, phosphorylation, deamidation, and carbamylation. Many of these modifications occur early in life and are probably part of a programmed modification of the crystallins that is required for their long-term stability and functionality. There is evidence that certain of these processes (phosphorylation, thiol oxidation) are reversible and may serve a regulatory function, although this hypothesis remains to be proved.

It is known that as the proteins age (particularly in some cataracts), certain oxidative modifications accumulate, which contributes to the crosslinking of crystallin polypeptides, alterations in fluorescent properties, and an increase in protein-associated pigmentation. In particular, the formation of disulfide crosslinks in the proteins of the lens nuclear region is associated with the formation of protein aggregates, light scattering, and cataract.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.