FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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All :: 2011
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References
N-terminal domain of alphaB-crystallin provides a conformational switch for multimerization and structural heterogeneity
Jehle(*), S., Vollmar(*), B. S., Bardiaux, B., Dove(*), K. K., Rajagopal(*), P., Gonen(*), T., Oschkinat, H.; Klevit(*), R. E.
Proc Natl Acad Sci U S A, 108:6409-6414
(2011)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: The small heat shock protein (sHSP) alphaB-crystallin (alphaB) 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 alphaB oligomers. We present an atomic-level model of full-length alphaB 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 alpha-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 alphaB in negative-stain EM images and the known dynamic exchange of alphaB subunits. The model of alphaB provides a structural basis for understanding known disease-associated missense mutations and makes predictions concerning substrate binding and the reported fibrilogenesis of alphaB.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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