N-terminal domain of αB-crystallin provides a conformational switch for multimerization and structural heterogeneity

The small heat shock protein (sHSP) αB-crystallin (αB) plays a key role in the cellular protection system against stress. For decades, high-resolution structural studies on heterogeneous sHSPs have been confounded by the polydisperse nature of αB oligomers. We present an atomic-level model of full-l...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2011-04, Vol.108 (16), p.6409-6414
Main Authors: Jehle, Stefan, Vollmar, Breanna S., Bardiaux, Benjamin, Dove, Katja K., Rajagopal, Ponni, Gonen, Tamir, Oschkinat, Hartmut, Klevit, Rachel E., Horwich, Arthur L.
Format: Article
Language:English
Subjects:
Alzheimers disease
Arithmetic mean
Biological Sciences
Chemical equilibrium
Crystal structure
Dimers
Electron microscopy
Eye lens
Oligomers
Proteins
Small heat shock proteins
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Summary:The small heat shock protein (sHSP) αB-crystallin (αB) plays a key role in the cellular protection system against stress. For decades, high-resolution structural studies on heterogeneous sHSPs have been confounded by the polydisperse nature of αB oligomers. We present an atomic-level model of full-length αB as a symmetric 24-subunit multimer based on solid-state NMR, small-angle X-ray scattering (SAXS), and EM data. The model builds on our recently reported structure of the homodimeric a-crystallin domain (ACD) and C-terminal IXI motif in the context of the multimer. A hierarchy of interactions contributes to build multimers of varying sizes: Interactions between two ACDs define a dimer, three dimers connected by their C-terminal regions define a hexameric unit, and variable interactions involving the N-terminal region define higher-order multimers. Within a multimer, N-terminal regions exist in multiple environments, contributing to the heterogeneity observed by NMR. Analysis of SAXS data allows determination of a heterogeneity parameter for this type of system. A mechanism of multimerization into higher-order asymmetric oligomers via the addition of up to six dimeric units to a 24-mer is proposed. The proposed asymmetric multimers explain the homogeneous appearance of αB in negative-stain EM images and the known dynamic exchange of αB subunits. The model of αB provides a structural basis for understanding known disease-associated missense mutations and makes predictions concerning substrate binding and the reported fibrilogenesis of αB.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1014656108