Preferential and specific binding of human αb-crystallin to a cataract-related variant of γs-crystallin

Carolyn N. Kingsley, William D. Brubaker, Stefan Markovic, Anne Diehl, Amanda J. Brindley, Hartmut Oschkinat, Rachel W. Martin

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Transparency in the eye lens is maintained via specific, functional interactions among the structural βγ- and chaperone α-crystallins. Here, we report the structure and α-crystallin binding interface of the G18V variant of human γS-crystallin (γS-G18V), which is linked to hereditary childhood-onset cortical cataract. Comparison of the solution nuclear magnetic resonance structures of wild-type and G18V γS-crystallin, both presented here, reveal that the increased aggregation propensity of γS-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.

Original languageEnglish (US)
Pages (from-to)2221-2227
Number of pages7
JournalStructure
Volume21
Issue number12
DOIs
StatePublished - Dec 3 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank Wytze van der Veer for assistance with optical data collection and Doug Tobias and Melanie Cocco for helpful discussions. This work was supported by National Institutes of Health grant 1R01EY021514 (to R.W.M.) and a Deutsche Forschungsgemeinschaft grant within the frame of the SFB 740 (to H.O.).

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