@article {3629,
	title = {N-terminal domain of alphaB-crystallin provides a conformational switch for multimerization and structural heterogeneity.},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {108},
	year = {2011},
	month = {2011 Apr 19},
	pages = {6409-14},
	abstract = {<p>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.</p>
},
	keywords = {alpha-Crystallin B Chain, Animals, Biomolecular, Humans, Missense, Models, Molecular, Mutation, Nuclear Magnetic Resonance, Protein Multimerization, Protein Structure, Quaternary, Tertiary},
	issn = {1091-6490},
	doi = {10.1073/pnas.1014656108},
	author = {Jehle, Stefan and Vollmar, Breanna S and Bardiaux, Benjamin and Dove, Katja K and Rajagopal, Ponni and Gonen, Tamir and Oschkinat, Hartmut and Klevit, Rachel E}
}
