Preferential and Specific Binding of Human αB-Crystallin to a Cataract-Related Variant of S-Crystallin
Carolyn N. Kingsley, William D. Brubaker, Stefan Markovic, Anne Diehl, Amanda J. Brindley, Hartmut Oschkinat, Rachel W. Martin
Transparency in the eye lens is maintained via specific, functional interactions among the structural β- and chaperone α-crystallins. Here, we report the structure and α-crystallin binding interface of the G18V variant of human S-crystallin (S-G18V), which is linked to hereditary childhood-onset cortical cataract. Comparison of the solution nuclear magnetic resonance structures of wild-type and G18V S-crystallin, both presented here, reveal that the increased aggregation propensity of S-G18V results from neither global misfolding nor the solvent exposure of a hydrophobic residue but instead involves backbone rearrangement within the N-terminal domain. αB-crystallin binds more strongly to the variant, via a well-defined interaction surface observed via chemical shift differences. In the context of the αB-crystallin structure and the finding that it forms heterogeneous multimers, our structural studies suggest a potential mechanism for cataract formation via the depletion of the finite αB-crystallin population of the lens.
