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J Mol Biol. 2018 Sep 14;430(18 Pt B):3297-3310. doi: 10.1016/j.jmb.2018.06.047. Epub 2018 Jun 30.

Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3.

Author information

1
Department of Biological Sciences, Crystallography, Institute of Structural & Molecular Biology, Birkbeck College, Malet Street, London, WC1E 7HX, UK.
2
Radboud University Nijmegen, Institute of Molecules & Materials, Department of Biomol Chem, NL-6500 Nijmegen, Netherlands.
3
Department of Chemistry, Physical & Theoretical Chemistry Laboratory, University of Oxford, South Parks Rd, Oxford, OX1 3QZ, UK.
4
Research School of Chemistry, Australian National University, Acton, ACT, 2601, Australia.
5
Department of Biological Sciences, Crystallography, Institute of Structural & Molecular Biology, Birkbeck College, Malet Street, London, WC1E 7HX, UK. Electronic address: n.keep@mail.cryst.bbk.ac.uk.

Abstract

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.

KEYWORDS:

asymmetric heteromer; heat shock protein; molecular chaperone; polydispersity; α-crystallin domain

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