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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Jehle, Stefan Dove, Katja K. Oschkinat, Hartmut Vollmar, Breanna S. Rajagopal, Ponni Bardiaux, Benjamin Gonen, Tamir Klevit, Rachel E. |
| Description | Author Affiliation: Jehle S ( Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.); |
| Abstract | The small heat shock protein (sHSP) B-crystallin ( B) 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 B oligomers. We present an atomic-level model of full-length B 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 -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 B in negative-stain EM images and the known dynamic exchange of B subunits. The model of B provides a structural basis for understanding known disease-associated missense mutations and makes predictions concerning substrate binding and the reported fibrilogenesis of B. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 16 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Models, Molecular Protein Multimerization Alpha-Crystallin B Chain Chemistry Animals Mutation, Missense Nuclear Magnetic Resonance, Biomolecular Protein Structure, Quaternary Protein Structure, Tertiary Genetics Metabolism Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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