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Terminal regions confer plasticity to the tetrameric assembly of human HspB2 and HspB3
Clark, Alice R Vree Egberts, Wilma Kondrat, Frances DL Hilton, Gillian R Ray, Nicholas J Cole, Ambrose R Carver, John A Benesch, Justin LP Keep, Nicholas H Boelens, Wilbert C
Clark, Alice R
Vree Egberts, Wilma
Kondrat, Frances DL
Hilton, Gillian R
Ray, Nicholas J
Cole, Ambrose R
Carver, John A
Benesch, Justin LP
Keep, Nicholas H
Boelens, Wilbert C
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2018-06-30
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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.
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Clark, A.R., Egberts, W.V., Kondrat, F.D.L. et al. (2018) Terminal regions confer plasticity to the tetrameric assembly of human HspB2 and HspB3, Journal of Molecular Biology, 430(18, part B), pp. 3297-3310.
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Journal article
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© 2018 The Authors. Published by Elsevier. This is an open access article available under a Creative Commons licence.
The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.jmb.2018.06.047
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0022-2836
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C.S. is grateful for the financial support of the Medical Research Council, UK (grant G0801846), and the synchrotron beamline staff at the European Synchrotron Radiation Facility (Grenoble, France), the Diamond Light Source (Oxfordshire, UK) and Soleil, France (partially funded through BIOSTRUCT-X). J.L.P.B. acknowledges the Biotechnology and Biological Sciences Research Council (BB/J018082/1). J.A.C. acknowledges the support of the National Health and Medical Research Council of Australia (grant 1068087).