A new study reveals the likely mechanism that a protein called human α-crystallin uses to protect the lens of the eye from clouding or becoming opaque. The work could lead to new drugs to prevent cataract formation.
The human eye lens contains a protein called γD-crystallin that can unfold, oxidize, and aggregate to form cataracts. Human α-crystallin protects the lens by inhibiting γD-crystallin aggregation.
But how this so-called chaperone protein works on a molecular level has been a mystery. Because human α-crystallin is a large protein with a variable number of subunits, it has been difficult to use techniques such as nuclear magnetic resonance spectroscopy (NMR) to study the shape changes and binding interactions it undergoes as it performs its protective role.
In 2000, ophthalmology professor Krishna Sharma of the University of Missouri and coworkers discovered that mini-α-crystallin (MAC), a tiny 19-residue fragment of α-crystallin, has chaperone properties similar to those of the parent protein.
Recognizing that MAC is much easier to study than the parent protein, researchers have now probed it with NMR to see how MAC, and presumably α-crystallin as well, works its protective magic. The study was carried out by chemistry professors Jayanti Pande and Alexander Shekhtman and coworkers at the University at Albany (Biochemistry 2014, DOI: 10.1021/bi5014479).
The study suggests that MAC prevents cataracts by binding weakly to the exterior of natively folded γD-crystallin and then moving to the interior when heat or chemical stress causes γD-crystallin to unfold.
“The lower-affinity binding to sites on the native state suggests a two-state recognition process, which would be kinetically very efficient, in which a weakly bound chaperone scans the protein for unfolded regions,” comments Jonathan King, a crystallin and protein misfolding specialist at Massachusetts Institute of Technology. “The authors’ NMR data directly identify interactions with buried core residues presumably exposed during unfolding.”
Because human α-crystallin likely shares this mechanism, at least to some extent, the work gives a first molecular view of the mechanism of action of the lens-protective parent protein.
The findings could thus aid the design of MAC mimics as anticataract drug candidates. “For example, you could make a D-amino acid version of MAC that would have a longer half-life in the body,” Sharma comments.