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Title: Structural and biochemical studies of human HSPB6 – a model sHSP for characterising the active chaperone state
Authors: Weeks, Stephen
Heirbaut, Michelle
Beelen, Steven
Strelkov, Sergei
Issue Date: Aug-2013
Conference: International Congress on Stress Proteins in Biology and Medicine edition:6 location:Sheffield, UK date:18-22 August, 2013
Abstract: Small heat-shock proteins (sHSPs) are an important component of the cellular chaperoning machinery, binding partially unfolded proteins and preventing their irreversible aggregation. Canonical sHSPs, such as the α-crystallins, form large polydisperse and dynamic oligomers. The latter property is believed to be essential for activity. Models of sHSP action propose the dissociation of a smaller, chaperoning competent subspecies, that binds substrate before reassociating with the larger oligomer. To obtain a better picture of this functional species, we have focused our efforts on biophysically and biochemically characterising human HSPB6 which, despite having considerable homology to the α-crystallins, only forms dimers in solution. By combining the crystal structure of a proteolytically stable fragment with small angle X-ray scattering data of the full-length protein, we have derived a molecular model of HSPB6. The crystal structure reveals α-crystallin domain (ACD) dimers that show extensive inter-dimer patching of the conserved β4/β8 grooves. Surprisingly this patching is mediated by motifs N-terminal to the ACD. In solution, HSPB6 shows a strong attractive self-interaction, a property that correlates with chaperoning activity. Both properties are dictated by the N-terminal domain (NTD), specifically a region highly conserved across
vertebrate sHSPs and linked to similar roles in the α-crystallins. The integrated structural studies of HSPB6 thus provide the first model of the putative active state of a vertebrate sHSP. Using this structure as a template we have performed additional biochemical and biophysical deletion mapping studies to elucidate the role of various regions in the NTD involved in chaperoning and hetero-oligomerisation with human HSPB1.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Biocrystallography

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