Binding Between Ocular Lens Crystallins Linked to Cataract Formation
Abstract
As biological resistance against cataracts, proteins called α-crystallins in the lens of the eye are present to keep denatured crystallins from precipitating and forming cataracts. Over time, these α-crystallins are increasingly bound to denatured proteins and contribute to the conglomeration of other crystallins themselves. Since the eye does not replace these essential proteins, the incidence of cataract formation increases without α-crystallin binding. Biochemists at the University of California-Irvine have recently observed trends in αB-crystallins’ interaction with structural γS-crystallin variations, which established a connection between cataract formation and the absence of the αB-crystallin. Molecular discoveries regarding αB-crystallin and γS-crystallin structures have also introduced the possibility of developing protein-specific drugs and corrective treatment for cataracts, as well as providing more widely available options for lower-income global populations.
Introduction
Cataracts are becoming increasingly prevalent in the aging world population. A study published in 2010 by the World Health Organization quoted the occurrence of visual impairment worldwide at 285 million; of these, 33% of avoidable visual impairment cases and 51% of avoidable blindness cases are caused solely by cataracts (Visual Impairment and Blindness 2010, S.P. Mariotti et al.). As defined by the American Optometric Association, cataracts are “…a cloudy or opaque area in the normally clear lens of the eye” that can cause deteriorating eyesight due to the obstruction of light passage to the retina (“Cataracts”, American Optometric Association). The lens is composed of different proteins known as α-, β-, and γ-crystallins. The figure below illustrates the various types of crystallins (Crystallins, Research Collaboratory for Structural Bioinformatics).

Although termed “crystallins,” these proteins maintain fluidity and transparency in the eye necessary for light to reach the retina. The body produces natural defenses against the formation of cataracts in the form of α-crystallins, which function as both structural and regulatory proteins (Crystallins, Research Collaboratory for Structural Bioinformatics). These α-crystallins are able to regulate crystallin aggregation in the eye via heat shock protein properties, allowing the body to indicate the presence of denatured crystallins through temperature stress signals. In contrast, γ- and β-crystallins function exclusively as structural proteins. They share a similar structure known as Greek key beta sheets, due to the strands’ unique shape caused by hydrogen bonds. β-crystallins are able to form oligomers, while the simple monomer γ-crystallins serve to hold structural α-crystallins together. Since α-crystallins are the most common crystallin found in the lens, their ability to keep the rest of the crystallins in check is vital to the health of the eye (α-Crystallin Modulates its Chaperone Activity by Varying the Exposed Surface, V. Palmieri et al.). The carboxyl tail domain, or C-terminal domain, of α-crystallin defines the protein because of its carboxyl group’s alpha positioning. Since the carboxyl group is hydrophilic, the α-crystallin is water-soluble and keeps the fluidity of the lens in check even when bound to denatured crystallins. With a denatured α-crystallin, solubility is compromised and insoluble aggregates begin to form cataracts. The finite nature of these chaperone-capable α-crystallins enforces the need for a secondary preventative form of regulation.
Methods of Investigation
In studies performed at the University of California-Irvine, the two most abundant crystallins (αB-crystallins and γS-crystallins) were studied to determine the effects of the proteins’ structure on intermolecular interactions. Through nuclear magnetic resonance, or NMR, the structure of these crystallins became apparent. The α-crystallins are defined by short, polar, highly-flexible and solvent-exposed C-terminal extensions in each of the subunits (“NMR Spectroscopy of Alpha-Crystallin”, J. A. Carver et al.). The γS-crystallins differ in pi-pi interactions, due to a malformation that caused the molecules to form with different side chains than normal γS-crystallins. The γS-crystallin variations included both healthy crystallins and mutated crystallins, the latter of which has been connected to genetic childhood cataract formation. The figure below is a representation of the difference in interactions between mutated and normal γS-crystallins with αB-crystallins (Preferential and Specific Binding of αB-Crystallin to a Cataract-Related Variant of γS-Crystallin, C. Kingsley et al.).

In medicine, these pi-stacking differences play a large role in the way proteins and small molecules interact with drugs. With new knowledge of the intermolecular interactions occurring between crystallins, chemists may be able to develop drugs to target specific γ-crystallins whose molecular structure prevents chaperone intervention by α-crystallins (Preferential and Specific Binding of αB-Crystallin to a Cataract-Related Variant of γS-Crystallin, C. Kingsley et al.). In this way, α-crystallins will be aided by medication to continue regulating denatured proteins and prevent aggregation. Since α-crystallins maintain fluidity while bound to denatured proteins, interventional medication would need to possess similar chemical properties to their α-crystallin counterparts to avoid aggregation.
Global Applications If developed, cataract prevention could possibly be distributed in the form of oral medications or medicated artificial lenses. Less-developed nations would not need surgically trained professionals to treat afflicted populations, making treatment more widespread and readily available. The price of such treatments would likely be more cost-effective than surgical intervention as well. Low and middle income populations would have much more access to pharmaceutical solutions, increasing their quality of life. Preventative measures to avoid crystallin aggregation and cataract formation could ultimately reduce the number of individuals with irreversible eye damage, which the aging global population would greatly benefit from. In a world that is also increasingly dependent on artificially backlit technology, the early damage suffered by younger populations would be reparable. As the only organs responsible for the sense of sight, preservation of lens fluidity and further understanding of ocular crystallins are essential to the best interests of people worldwide.

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