Wrapping the α-Crystallin Domain Fold in a Chaperone Assembly

• Published in: Journal of molecular biology 2005-10, Vol.353 (1), p.68-79
• Main Authors: Stamler, Robin, Kappé, Guido, Boelens, Wilbert, Slingsby, Christine
• Format: Article
• Language: English
• Subjects: alpha-Crystallins - chemistry; alpha-Crystallins - genetics; alpha-Crystallins - metabolism; Amino Acid Sequence; Animals; Crystallography, X-Ray; Echinococcus multilocularis; Heat-Shock Proteins - chemistry; Heat-Shock Proteins - metabolism; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; molecular chaperone; Molecular Chaperones - chemistry; Molecular Chaperones - metabolism; Molecular Sequence Data; Protein Binding; Protein Folding; Protein Structure, Quaternary; Protein Structure, Tertiary; Schistosoma mansoni; Sequence Alignment; small heat shock protein; Taenia saginata - chemistry; α-crystallin
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2005.08.025

Small heat shock proteins (sHsps) are oligomers that perform a protective function by binding denatured proteins. Although ubiquitous, they are of variable sequence except for a C-terminal ∼90-residue “α-crystallin domain”. Unlike larger stress response chaperones, sHsps are ATP-independent and generally form polydisperse assemblies. One proposed mechanism of action involves these assemblies breaking into smaller subunits in response to stress, before binding unfolding substrate and reforming into larger complexes. Two previously solved non-metazoan sHsp multimers are built from dimers formed by domain swapping between the α-crystallin domains, adding to evidence that the smaller subunits are dimers. Here, the 2.5 Å resolution structure of an sHsp from the parasitic flatworm Taenia saginata Tsp36, the first metazoan crystal structure, shows a new mode of dimerization involving N-terminal regions, which differs from that seen for non-metazoan sHsps. Sequence differences in the α-crystallin domains between metazoans and non-metazoans are critical to the different mechanism of dimerization, suggesting that some structural features seen for Tsp36 may be generalized to other metazoan sHsps. The structure also indicates scope for flexible assembly of subunits, supporting the proposed process of oligomer breakdown, substrate binding and reassembly as the chaperone mechanism. It further shows how sHsps can bind coil and secondary structural elements by wrapping them around the α-crystallin domain. The structure also illustrates possible roles for conserved residues associated with disease, and suggests a mechanism for the sHsp-related pathogenicity of some flatworm infections. Tsp36, like other flatworm sHsps, possesses two divergent sHsp repeats per monomer. Together with the two previously solved structures, a total of four α-crystallin domain structures are now available, giving a better definition of domain boundaries for sHsps.