Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3
| Autor: | Wilbert C. Boelens, Frances D.L. Kondrat, Nicholas J. Ray, Nicholas H. Keep, Ambrose R. Cole, Gillian R. Hilton, Christine Slingsby, Wilma Vree Egberts, Alice R. Clark, John A. Carver, Justin L. P. Benesch |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Magnetic Resonance Spectroscopy α-crystallin domain Protein Conformation Dimer heat shock protein HSP27 Heat-Shock Proteins Heteromer Plasticity bcs AP anti-parallel Article 03 medical and health sciences chemistry.chemical_compound polydispersity Tetramer Structural Biology Heat shock protein Humans Protein Interaction Domains and Motifs Amino Acid Sequence Molecular Biology Heat-Shock Proteins biology asymmetric heteromer Bio-Molecular Chemistry Atomic coordinates molecular chaperone Protein tertiary structure TOCSY total correlated spectroscopy 3. Good health 030104 developmental biology MS mass spectrometry chemistry Chaperone (protein) ACD α-crystallin domain Biophysics biology.protein Protein Multimerization sHSP small heat shock protein Protein Binding |
| Zdroj: | Journal of Molecular Biology, 430, 3297-3310 'Journal of Molecular Biology ', vol: 430, pages: 3297-3310 (2018) Journal of Molecular Biology Journal of Molecular Biology, 430, 18, pp. 3297-3310 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2018.06.047 |
| Popis: | Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes—from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterization. Atomic coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallized as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four α-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible “nuts and bolts” involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps. Graphical abstract Unlabelled Image Highlights • Dynamic behavior of heteromeric sHsps hinders structural biology of cytoprotection. • Full-length human HspB2/B3 in 3:1 ratio was crystallized and solved at 3.9-Å resolution. • Assembly is by flexible “nuts and bolts” from terminal regions filling domain pockets. • N-terminal regions bind in an unfolded conformation into shared dimer grooves. • IXI/V motifs from unstructured proteins may be sequestered by sHsps during disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect