Multiple molecular architectures of the eye lens chaperone αB-crystallin elucidated by a triple hybrid approach.

The molecular chaperone αB-crystallin, the major player in maintaining the transparency of the eye lens, prevents stress-damaged and aging lens proteins from aggregation. In nonlenticular cells, it is involved in various neurological diseases, diabetes, and cancer. Given its structural plasticity and dynamics, structure analysis of αB-crystallin presented hitherto a formidable ...
challenge. Here we present a pseudoatomic model of a 24-meric αB-crystallin assembly obtained by a triple hybrid approach combining data from cryoelectron microscopy, NMR spectroscopy, and structural modeling. The model, confirmed by cross-linking and mass spectrometry, shows that the subunits interact within the oligomer in different, defined conformations. We further present the molecular architectures of additional well-defined αB-crystallin assemblies with larger or smaller numbers of subunits, provide the mechanism how "heterogeneity" is achieved by a small set of defined structural variations, and analyze the factors modulating the oligomer equilibrium of αB-crystallin and thus its chaperone activity.
Mesh Terms:
Cross-Linking Reagents, Cryoelectron Microscopy, Heat-Shock Proteins, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Lens, Crystalline, Magnetic Resonance Spectroscopy, Mass Spectrometry, Microscopy, Electron, Models, Molecular, Molecular Conformation, Mutagenesis, Site-Directed, Protein Conformation, Protein Structure, Secondary, alpha-Crystallin B Chain
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 20, 2011
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