title: Preferential and specific binding of human αB-crystallin to a cataract-related variant of γS-crystallin.
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.
authors.affiliation: Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, USA.
authors.forename: Carolyn N
authors.initials: CN
authors.lastname: Kingsley
authors.forename: William D
authors.initials: WD
authors.lastname: Brubaker
authors.forename: Stefan
authors.initials: S
authors.lastname: Markovic
authors.forename: Anne
authors.initials: A
authors.lastname: Diehl
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Brindley
authors.forename: Hartmut
authors.initials: H
authors.lastname: Oschkinat
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Martin
mesh_terms: D002386:Cataract / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D038203:alpha-Crystallin B Chain / Q000737:chemistry*; D038222:gamma-Crystallins / Q000737:chemistry* / Q000235:genetics
chemical_list: D038203:alpha-Crystallin B Chain; D038222:gamma-Crystallins; C077648:CRYGS protein, human