6f2r
A heterotetramer of human HspB2 and HspB3
Structural highlights
Disease[HSPB3_HUMAN] Distal hereditary motor neuropathy type 2. The disease is caused by mutations affecting the gene represented in this entry. Function[HSPB2_HUMAN] May regulate the kinase DMPK.[1] [HSPB3_HUMAN] Inhibitor of actin polymerization. Publication Abstract from PubMedHeterogeneity 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 alpha-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. Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3.,Clark AR, Vree Egberts W, Kondrat FDL, Hilton GR, Ray NJ, Cole AR, Carver JA, Benesch JLP, Keep NH, Boelens WC, Slingsby C J Mol Biol. 2018 Sep 14;430(18 Pt B):3297-3310. doi: 10.1016/j.jmb.2018.06.047., Epub 2018 Jun 30. PMID:29969581[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
