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Terminal regions confer plasticity to the tetrameric assembly of human HspB2 and HspB3

DOI: 10.1016/j.jmb.2018.06.047 DOI Help

Authors: Alice Clark (Birkbeck College, University of London) , Wilma Vree Egberts (Radboud University Nijmegen) , Frances D. L. Kondrat (University of Oxford) , Gillian R. Hilton (University of Oxford) , Nicholas J. Ray (Australian National University) , Ambrose R. Cole (Birkbeck College, University of London) , John A. Carver (Australian National University) , Justin L. P. Benesch (University of Oxford) , Nicholas Keep (Birkbeck College, University of London) , Wilbert C. Boelens (Radboud University Nijmegen) , Christine Slingsby (Birkbeck College, University of London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: June 2018
Diamond Proposal Number(s): 7197

Open Access Open Access

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 characterisation. 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 crystallised 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.

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

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility; Soleil

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