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| Title | N-terminal domain of alphaB-crystallin provides a conformational switch for multimerization and structural heterogeneity. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 108, Issue 16, Page 6409-6414, Year 2011 |
| Publish date | Apr 19, 2011 |
 Authors | Stefan Jehle / Breanna S Vollmar / Benjamin Bardiaux / Katja K Dove / Ponni Rajagopal / Tamir Gonen / Hartmut Oschkinat / Rachel E Klevit /  |
| PubMed Abstract | 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 ...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 α-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. |
 External links | Proc Natl Acad Sci U S A / PubMed:21464278 / PubMed Central |
| Methods | NMR (solid-state) / small angle scattering / EM (single particle) |
| Resolution | 20 Å |
| Structure data |  PDB-3j07: |
| Source |
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 Keywords |  CHAPERONE / sHSP |
